Is SIM1 p.Ala371Val (c.1112C>T) pathogenic?

SIM1 p.Ala371Val (c.1112C>T) is classified Benign in SIM1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0729); Common (popmax 46%, eas) — too common for a highly-penetrant pathogenic allele; Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Ala371Val (c.1112C>T)?

SIM1 p.Ala371Val (c.1112C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

What do computational predictors say about SIM1 p.Ala371Val (c.1112C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

SIM1 p.Ala371Val

Q: How common is SIM1 p.Ala371Val (c.1112C>T) in the general population?

SIM1 p.Ala371Val (c.1112C>T) is common (popmax 46%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1112C>T · rs3734355 · VCV354680

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 46%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.35	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 2.7	GERP -1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	16.16	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 46% East Asian · 20,644/44,838 alleles

Filtering AF 45.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 45.3%

Overall 15% 241,474/1,613,556 alleles · common exomes 221,777/1,461,412 · genomes 19,697/152,144 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	46%	2
Admixed American	24%	4
Finnishnot grpmax-eligible	18.3%	5
South Asian	16.6%	6
Remaining individualsnot grpmax-eligible	14.7%	7
European (non-Finnish)	13.9%	7
Amishnot grpmax-eligible	13.6%	7
Ashkenazi Jewishnot grpmax-eligible	12.4%	8
Middle Eastern	11.3%	9
African / African-American	2.7%	37

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.Ala371Val
Coding: c.1112C>T
MANE Select: NM_005068
dbSNP: rs3734355
Type: single nucleotide variant
Location: chr6:100420845 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 371: a UniProt-annotated variant site (in); the single-minded c-terminal domain; the 'disordered' region

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.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 p.Val76Ile Uncertain significance ★★ ⚠ same condition
SIM1 c.544-15A>C Benign ★★ same condition
SIM1 p.Arg665His Benign ★★ same condition
SIM1 p.Asn764= Benign/Likely 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-ala371val (accessed [today's date]).

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