Is SIM1 p.Ile313Val (c.937A>G) pathogenic?

SIM1 p.Ile313Val (c.937A>G) is classified Uncertain significance in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.00195%, nfe); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Ile313Val (c.937A>G)?

SIM1 p.Ile313Val (c.937A>G) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Ile313Val (c.937A>G) in the general population?

SIM1 p.Ile313Val (c.937A>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about SIM1 p.Ile313Val (c.937A>G)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

SIM1 p.Ile313Val

c.937A>G · VCV3355618

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIM1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -8.93	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 5.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 27 kb · p 4.7e-05 · regional, not allelic
Overall
CADD	23.3	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 0.00195% European (non-Finnish) · 23/1,180,034 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,614,186 alleles · very rare exomes 25/1,461,890 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,306
Admixed American	0.00167%	60,024
African / African-American	0.00133%	75,050

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.Ile313Val
Coding: c.937A>G
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100447329 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 313: the pac 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-ile313val (accessed [today's date]).

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