Is SIM1 p.Cys272= (c.816C>T) pathogenic?

SIM1 p.Cys272= (c.816C>T) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 8.48e-05%, nfe); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Cys272= (c.816C>T)?

SIM1 p.Cys272= (c.816C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Cys272= (c.816C>T) in the general population?

SIM1 p.Cys272= (c.816C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

SIM1 p.Cys272=

c.816C>T · rs764549841 · VCV354682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -4.6, phastCons 0.002
Overall
CADD	10.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,914 alleles

Overall 6.2e-05% 1/1,613,704 alleles · very rare exomes 1/1,461,322 · genomes 0/152,382 · joint denominator

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.Cys272=
Coding: c.816C>T
MANE Select: NM_005068
dbSNP: rs764549841
Type: single nucleotide variant
Location: chr6:100448180 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 272: the pas 2 domain

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.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-cys272 (accessed [today's date]).

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