Is SGCA p.Pro227Arg (c.680C>G) pathogenic?

SGCA p.Pro227Arg (c.680C>G) is classified Conflicting classifications of pathogenicity in SGCA (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.1047); Ultra-rare (popmax 0.0825%, mid); Associated with sarcoglycanopathy.

What condition is associated with SGCA p.Pro227Arg (c.680C>G)?

SGCA p.Pro227Arg (c.680C>G) is associated with sarcoglycanopathy, autosomal recessive limb-girdle muscular dystrophy type 2D (ClinVar).

How common is SGCA p.Pro227Arg (c.680C>G) in the general population?

SGCA p.Pro227Arg (c.680C>G) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about SGCA p.Pro227Arg (c.680C>G)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

SGCA p.Pro227Arg

c.680C>G · rs201131924 · VCV198033

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

sarcoglycanopathy

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -7.26	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 3.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic
Overall
CADD	21.8	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 0.0825% Middle Eastern · 5/6,060 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0219% 354/1,614,034 alleles · ultra-rare exomes 318/1,461,822 · genomes 36/152,212 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0256%	3,906
European (non-Finnish)	0.025%	4,000
African / African-American	0.00533%	18,749
Finnishnot grpmax-eligible	0.00313%	32,000
South Asian	0.0022%	45,541

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.Pro227Arg
Coding: c.680C>G
MANE Select: NM_000023
dbSNP: rs201131924
Type: single nucleotide variant
Location: chr17:50169187 (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

sarcoglycanopathy — 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.Pro227= Likely benign ★ 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
SGCA p.Arg221Pro 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-pro227arg (accessed [today's date]).

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