Is SIM1 p.Ala688Val (c.2063C>T) pathogenic?

SIM1 p.Ala688Val (c.2063C>T) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely benign (0.0745); Very rare (popmax 0.00891%, eas).

How common is SIM1 p.Ala688Val (c.2063C>T) in the general population?

SIM1 p.Ala688Val (c.2063C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about SIM1 p.Ala688Val (c.2063C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

SIM1 p.Ala688Val

c.2063C>T · VCV3716933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.70	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 0.68, phastCons 0.084
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	14.99	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 0.00891% East Asian · 4/44,882 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000743% 12/1,614,168 alleles · very rare exomes 9/1,461,860 · genomes 3/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
South Asian	0.00878%	11,385

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: SIM1
Protein: p.Ala688Val
Coding: c.2063C>T
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100390599 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 688: the single-minded c-terminal domain

Full SIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIM1 p.Cys434Ter Pathogenic ★★ same type
SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same type
SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same type
SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same type
SIM1 p.Arg550His Uncertain significance ★★ ⚠ same type
SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same type
SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same type
SIM1 p.Glu552Lys Uncertain significance ★★ ⚠ 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/sim1-p-ala688val (accessed [today's date]).

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