Is SIM1 p.Val76Ile (c.226G>A) pathogenic?

SIM1 p.Val76Ile (c.226G>A) is classified Uncertain significance in SIM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-06). AlphaMissense: likely benign (0.0896); Ultra-rare (popmax 0.033%, mid); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Val76Ile (c.226G>A)?

SIM1 p.Val76Ile (c.226G>A) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Val76Ile (c.226G>A) in the general population?

SIM1 p.Val76Ile (c.226G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about SIM1 p.Val76Ile (c.226G>A)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

SIM1 p.Val76Ile

c.226G>A · rs756912317 · VCV904787

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	22.3	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 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000434% 7/1,612,144 alleles · ultra-rare exomes 7/1,459,900 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.0016%	62,426
European (non-Finnish)	0.000339%	294,788

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.Val76Ile
Coding: c.226G>A
MANE Select: NM_005068
dbSNP: rs756912317
Type: single nucleotide variant
Location: chr6:100453794 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70

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

Disease context

obesity due to SIM1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Val76Leu Uncertain significance ★ ⚠ same residue
SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same condition
SIM1 p.Leu332Phe Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser622Phe Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser680Leu Uncertain significance ★★ ⚠ same condition
SIM1 c.544-15A>C Benign ★★ same condition
SIM1 p.Ala371Val Benign ★★ same condition
SIM1 p.Arg665His Benign ★★ 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-val76ile (accessed [today's date]).

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