Is SIM1 p.Ile682Val (c.2044A>G) pathogenic?

SIM1 p.Ile682Val (c.2044A>G) is classified Uncertain significance in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.0586); Ultra-rare (popmax 0.0133%, amr); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Ile682Val (c.2044A>G)?

SIM1 p.Ile682Val (c.2044A>G) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Ile682Val (c.2044A>G) in the general population?

SIM1 p.Ile682Val (c.2044A>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about SIM1 p.Ile682Val (c.2044A>G)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

SIM1 p.Ile682Val

c.2044A>G · rs756219222 · VCV3051546

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIM1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -5.99	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 0.72	GERP 0.14, phastCons 0.97
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	10.06	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 0.0133% Admixed American · 8/60,008 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00124% 20/1,614,102 alleles · ultra-rare exomes 19/1,461,894 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
South Asian	0.0132%	7,591

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.Ile682Val
Coding: c.2044A>G
MANE Select: NM_005068
dbSNP: rs756219222
Type: single nucleotide variant
Location: chr6:100390618 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 682: the single-minded c-terminal domain

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

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser199Cys Uncertain significance ★★ same condition
SIM1 p.Gly480Ter Likely pathogenic ★ same condition
SIM1 c.-468+6T>A Uncertain significance ★ same condition
SIM1 p.Ala484Ser Uncertain significance ★ ⚠ same condition
SIM1 p.Asn608Asp Uncertain significance ★ ⚠ same condition
SIM1 p.Lys287Arg Uncertain significance ★ ⚠ same condition
SIM1 p.Pro30Ala 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/sim1-p-ile682val (accessed [today's date]).

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