Is SI p.Ala706Val (c.2117C>T) pathogenic?

SI p.Ala706Val (c.2117C>T) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-14). AlphaMissense: ambiguous (0.4622); Ultra-rare (popmax 0.0198%, sas).

How common is SI p.Ala706Val (c.2117C>T) in the general population?

SI p.Ala706Val (c.2117C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about SI p.Ala706Val (c.2117C>T)?

AlphaMissense predicts ambiguous (score 0.4622) — an in-silico prediction, not a clinical call.

SI p.Ala706Val

c.2117C>T · rs753557397 · VCV1522711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4622 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4622	ambiguous
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -8.79	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	27.8	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 0.0198% South Asian · 18/91,044 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00124% 20/1,612,146 alleles · ultra-rare exomes 20/1,459,976 · genomes 0/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,058
European (non-Finnish)	0.00017%	589,286

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.Ala706Val
Coding: c.2117C>T
MANE Select: NM_001041
dbSNP: rs753557397
Type: single nucleotide variant
Location: chr3:165040982 (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 706: the 'isomaltase' region; an α-helix

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

Similar variants

SI c.2426+1G>A Likely pathogenic ★★ same type
SI c.2737-2A>G Likely pathogenic ★★ same type
SI c.2893-1G>A Likely pathogenic ★★ same type
SI c.3099+1G>C Likely pathogenic ★★ same type
SI c.3521-1G>T Likely pathogenic ★★ same type
SI c.373+1G>A Likely pathogenic ★★ same type
SI c.4575+2T>C Likely pathogenic ★★ same type
SI c.4927-1G>A Likely pathogenic ★★ 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/si-p-ala706val (accessed [today's date]).

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