Is SGCD p.Arg31Trp (c.91C>T) pathogenic?

SGCD p.Arg31Trp (c.91C>T) is classified Uncertain significance in SGCD (ClinVar, Expert panel, 5 submitters; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.9796); Ultra-rare (popmax 0.0165%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with SGCD p.Arg31Trp (c.91C>T)?

SGCD p.Arg31Trp (c.91C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2F, dilated cardiomyopathy 1L (ClinVar).

How common is SGCD p.Arg31Trp (c.91C>T) in the general population?

SGCD p.Arg31Trp (c.91C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SGCD p.Arg31Trp (c.91C>T)?

AlphaMissense predicts likely pathogenic (score 0.9796) — an in-silico prediction, not a clinical call.

SGCD p.Arg31Trp

c.91C>T · rs202223676 · VCV652862

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Uncertain Significance for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PP3

Curation rationale (ClinGen, verbatim)

The NM_000337.6: c.91C>T variant in SGCD is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 31 (p.Arg31Trp). The highest minor allele frequency for this variant is 0.00009898 in the South Asian population of gnomAD v2.1.1 (3/30310 exome chromosomes), which is higher than the LGMD VCEP threshold for PM2_Supporting (0.00009) (criterion not met). The computational predictor REVEL gives a score of 0.835, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCD function (PP3). In summary, at this time there is insufficient evidence to classify this variant as pathogenic or benign, and it remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9796	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -12.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -2.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 430 kb · p 0.031 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R30W vs ClinVar R31W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,064 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00155% 25/1,609,532 alleles · ultra-rare exomes 23/1,457,496 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,064
South Asian	0.00552%	18,132
Remaining individualsnot grpmax-eligible	0.00482%	20,726
East Asian	0.00447%	22,367
Finnishnot grpmax-eligible	0.0032%	31,260
African / African-American	0.00268%	37,383
European (non-Finnish)	0.000849%	117,843

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SGCD
Protein: p.Arg31Trp
Coding: c.91C>T
MANE Select: NM_000337
dbSNP: rs202223676
Type: single nucleotide variant
Location: chr5:156344576 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 81.43

Full SGCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2F dilated cardiomyopathy 1L

Similar variants

SGCD p.Arg31Gly Uncertain significance ★★★ ⚠ same residue
SGCD p.Arg31Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SGCD p.Arg31= Likely benign ★ same residue
SGCD p.Arg165Ter Pathogenic ★★★ same condition
SGCD p.Arg97Ter Pathogenic ★★★ same condition
SGCD p.Ile64Thr Uncertain significance ★★★ ⚠ same condition
SGCD c.192+1G>A Likely pathogenic ★★ same condition
SGCD c.294+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sgcd-p-arg31trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown