Is SI p.Ala760Val (c.2279C>T) pathogenic?

SI p.Ala760Val (c.2279C>T) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-13). AlphaMissense: ambiguous (0.4957); Ultra-rare (popmax 0.0362%, mid); Associated with Inborn genetic diseases.

What condition is associated with SI p.Ala760Val (c.2279C>T)?

SI p.Ala760Val (c.2279C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Ala760Val (c.2279C>T) in the general population?

SI p.Ala760Val (c.2279C>T) is ultra-rare (popmax 0.0362%, mid) (gnomAD).

What do computational predictors say about SI p.Ala760Val (c.2279C>T)?

AlphaMissense predicts ambiguous (score 0.4957) — an in-silico prediction, not a clinical call.

SI p.Ala760Val

c.2279C>T · rs757068502 · VCV1361647

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4957 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4957	ambiguous
REVEL	0.696	pathogenic-leaning
SaProt	LLR -12.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	25.9	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 0.0362% Middle Eastern · 2/5,522 alleles

Filtering AF 0.00634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00261%

Overall 0.00107% 17/1,593,342 alleles · ultra-rare exomes 16/1,441,328 · genomes 1/152,014 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0362%	2,761
Finnishnot grpmax-eligible	0.00313%	31,927
Remaining individualsnot grpmax-eligible	0.00162%	61,690
South Asian	0.00111%	90,360
European (non-Finnish)	0.000946%	105,717

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: SI
Protein: p.Ala760Val
Coding: c.2279C>T
MANE Select: NM_001041
dbSNP: rs757068502
Type: single nucleotide variant
Location: chr3:165039100 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 760: the 'isomaltase' region

Full SI 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

Similar variants

SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ same condition
SI p.Arg1078Gln Uncertain significance ★★ same condition
SI p.Arg1078Trp Uncertain significance ★★ ⚠ same condition
SI p.Arg1105Cys Uncertain significance ★★ ⚠ 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/si-p-ala760val (accessed [today's date]).

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