Is SGCA p.Val175Ile (c.523G>A) pathogenic?

SGCA p.Val175Ile (c.523G>A) is classified Uncertain significance in SGCA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-18). AlphaMissense: likely benign (0.0541); Very rare (popmax 0.00463%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2D.

What condition is associated with SGCA p.Val175Ile (c.523G>A)?

SGCA p.Val175Ile (c.523G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2D (ClinVar).

How common is SGCA p.Val175Ile (c.523G>A) in the general population?

SGCA p.Val175Ile (c.523G>A) is very rare (popmax 0.00463%, sas) (gnomAD).

What do computational predictors say about SGCA p.Val175Ile (c.523G>A)?

AlphaMissense predicts likely benign (score 0.0541) — an in-silico prediction, not a clinical call.

SGCA p.Val175Ile

Q: How is Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.523G>A · rs1472338684 · VCV2148037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00463%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2D

Computational evidence

Protein change
AlphaMissense	0.0541	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -1.8, phastCons 0.86
Regional constraint	o/e 0.91	unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic
Overall
CADD	13.14	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 0.00463% South Asian · 4/86,306 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000929%

Overall 0.00057% 9/1,579,966 alleles · very rare exomes 9/1,427,698 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00463%	21,577
Remaining individualsnot grpmax-eligible	0.00163%	61,220
European (non-Finnish)	0.000344%	290,608

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.Val175Ile
Coding: c.523G>A
MANE Select: NM_000023
dbSNP: rs1472338684
Type: single nucleotide variant
Location: chr17:50168511 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.15
Residue 175: a UniProt-annotated variant site (in lgmdr3)

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

SGCA p.Val175= Likely benign ★ same residue
SGCA p.Val175Ala Pathogenic 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.Arg221Cys 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-val175ile (accessed [today's date]).

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