Is SIM1 p.Leu88= (c.264G>A) pathogenic?

SIM1 p.Leu88= (c.264G>A) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). Ultra-rare (popmax 0.0505%, sas); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Leu88= (c.264G>A)?

SIM1 p.Leu88= (c.264G>A) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Leu88= (c.264G>A) in the general population?

SIM1 p.Leu88= (c.264G>A) is ultra-rare (popmax 0.0505%, sas) (gnomAD).

SIM1 p.Leu88=

c.264G>A · rs374914727 · VCV904786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, sas)

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 0.84	GERP 0.61, phastCons 1
Overall
CADD	11.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0505% South Asian · 46/91,080 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0348%

Overall 0.00316% 51/1,613,836 alleles · ultra-rare exomes 47/1,461,672 · genomes 4/152,164 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0505%	1,980
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.00167%	60,004

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.Leu88=
Coding: c.264G>A
MANE Select: NM_005068
dbSNP: rs374914727
Type: single nucleotide variant
Location: chr6:100450351 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 88: the pas 1 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-leu88 (accessed [today's date]).

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