Is SIM1 p.Asn764= (c.2292C>T) pathogenic?

SIM1 p.Asn764= (c.2292C>T) is classified Benign/Likely benign in SIM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-15). Rare (popmax 0.434%, afr); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Asn764= (c.2292C>T)?

SIM1 p.Asn764= (c.2292C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Asn764= (c.2292C>T) in the general population?

SIM1 p.Asn764= (c.2292C>T) is rare (popmax 0.434%, afr) (gnomAD).

SIM1 p.Asn764=

c.2292C>T · rs143803280 · VCV735341

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.434%, afr)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -0.027, phastCons 1
Overall
CADD	8.242	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.434% African / African-American · 325/74,874 alleles

Filtering AF 0.395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.38%

Overall 0.0395% 637/1,611,192 alleles · rare exomes 397/1,458,934 · genomes 240/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.434%	230
East Asian	0.276%	362
Remaining individualsnot grpmax-eligible	0.0561%	1,782
Admixed American	0.052%	1,924
South Asian	0.0353%	2,829
Middle Eastern	0.0166%	6,034
European (non-Finnish)	0.00755%	13,243

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.Asn764=
Coding: c.2292C>T
MANE Select: NM_005068
dbSNP: rs143803280
Type: single nucleotide variant
Location: chr6:100390370 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 764: the single-minded c-terminal 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-asn764 (accessed [today's date]).

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