Is GSC p.Ala26Val (c.77C>T) pathogenic?

GSC p.Ala26Val (c.77C>T) is classified Uncertain significance in GSC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.101); Very rare (popmax 0.00826%, afr).

How common is GSC p.Ala26Val (c.77C>T) in the general population?

GSC p.Ala26Val (c.77C>T) is very rare (popmax 0.00826%, afr) (gnomAD).

What do computational predictors say about GSC p.Ala26Val (c.77C>T)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

GSC p.Ala26Val

c.77C>T · rs1006202219 · VCV1925627

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00826%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,521 bp · p 0.91 · regional, not allelic
Overall
CADD	23.5	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 0.00826% African / African-American · 6/72,604 alleles

Filtering AF 0.00356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.000518% 8/1,544,680 alleles · very rare exomes 4/1,392,520 · genomes 4/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00826%	12,101
European (non-Finnish)	0.000173%	576,774

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: GSC
Protein: p.Ala26Val
Coding: c.77C>T
MANE Select: NM_173849
dbSNP: rs1006202219
Type: single nucleotide variant
Location: chr14:94769939 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.68 · 1 PDB

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

Similar variants

GSC p.Ala30Val Uncertain significance ★★ ⚠ same type
GSC p.Lys183Gln Uncertain significance ★★ ⚠ same type
GSC p.Tyr54Ser Uncertain significance ★★ ⚠ same type
GSC c.356-186C>T Benign ★★ same type
GSC p.Ala72Thr Benign ★★ same type
GSC p.Asn140= Benign/Likely benign ★★ same type
GSC p.Asp53= Benign/Likely benign ★★ same type
GSC p.Pro36= Benign ★★ same type

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/gsc-p-ala26val (accessed [today's date]).

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