Is SGCA p.Arg221Pro (c.662G>C) pathogenic?

SGCA p.Arg221Pro (c.662G>C) is classified Likely pathogenic in SGCA (ClinVar, Expert panel, 4 submitters; last evaluated 2025-01-07). AlphaMissense: likely pathogenic (0.6996); Very rare (popmax 6.2e-05%); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with SGCA p.Arg221Pro (c.662G>C)?

SGCA p.Arg221Pro (c.662G>C) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2D (ClinVar).

How common is SGCA p.Arg221Pro (c.662G>C) in the general population?

SGCA p.Arg221Pro (c.662G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SGCA p.Arg221Pro (c.662G>C)?

AlphaMissense predicts likely pathogenic (score 0.6996) — an in-silico prediction, not a clinical call.

SGCA p.Arg221Pro

c.662G>C · rs138254713 · VCV497670

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

PM2_Supporting PP4_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic 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; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong.

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

Computational evidence

Protein change
AlphaMissense	0.6996	likely pathogenic ✓ concordant with ClinVar
REVEL	0.765	pathogenic-leaning
SaProt	LLR -12.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,613,916 alleles · very rare exomes 1/1,461,770 · genomes 0/152,146 · joint denominator

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: SGCA
Protein: p.Arg221Pro
Coding: c.662G>C
MANE Select: NM_000023
dbSNP: rs138254713
Type: single nucleotide variant
Location: chr17:50169169 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.15

Full SGCA 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 2D

Similar variants

SGCA p.Arg221Cys Likely pathogenic ★★★ same residue
SGCA p.Arg221His Conflicting classifications of pathogenicity ★ ⚠ same residue
SGCA c.37+6T>C Pathogenic ★★★ same condition
SGCA c.585-1G>A Pathogenic ★★★ same condition
SGCA c.957-11C>G Likely pathogenic ★★★ same condition
SGCA p.Ala107Val Likely pathogenic ★★★ ⚠ same condition
SGCA p.Arg192Ter Pathogenic ★★★ same condition
SGCA p.Arg284Cys 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/sgca-p-arg221pro (accessed [today's date]).

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