Is SGCA p.Arg141His (c.422G>A) pathogenic?

SGCA p.Arg141His (c.422G>A) is classified Uncertain significance in SGCA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.00227%, eas); Associated with Inborn genetic diseases.

What condition is associated with SGCA p.Arg141His (c.422G>A)?

SGCA p.Arg141His (c.422G>A) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2D (ClinVar).

How common is SGCA p.Arg141His (c.422G>A) in the general population?

SGCA p.Arg141His (c.422G>A) is very rare (popmax 0.00227%, eas) (gnomAD).

What do computational predictors say about SGCA p.Arg141His (c.422G>A)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

SGCA p.Arg141His

c.422G>A · rs1325350236 · VCV448353

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP -1.3, phastCons 0.076
Regional constraint	o/e 0.91	unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% East Asian · 1/43,958 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.00044% 7/1,589,926 alleles · very rare exomes 6/1,437,826 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	43,958
South Asian	0.00115%	87,252
European (non-Finnish)	0.000428%	233,665

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.Arg141His
Coding: c.422G>A
MANE Select: NM_000023
dbSNP: rs1325350236
Type: single nucleotide variant
Location: chr17:50168410 (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

Inborn genetic diseases — 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.Arg141Cys Uncertain significance ★ ⚠ same residue
SGCA p.Arg141Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SGCA p.Arg141= Likely benign ★ same residue
SGCA p.Arg141Gly Uncertain significance ★ ⚠ 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

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-arg141his (accessed [today's date]).

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