Is SIM1 p.Phe93= (c.279C>T) pathogenic?

SIM1 p.Phe93= (c.279C>T) is classified Conflicting classifications of pathogenicity in SIM1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-14). Rare (popmax 0.165%, amr); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Phe93= (c.279C>T)?

SIM1 p.Phe93= (c.279C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Phe93= (c.279C>T) in the general population?

SIM1 p.Phe93= (c.279C>T) is rare (popmax 0.165%, amr) (gnomAD).

SIM1 p.Phe93=

c.279C>T · rs145361258 · VCV285978

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, amr)

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 0.14	GERP -4.2, phastCons 0.68
Overall
CADD	6.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Admixed American · 99/60,028 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.0995% 1,606/1,614,068 alleles · rare exomes 1,494/1,461,752 · genomes 112/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.165%	606
European (non-Finnish)	0.121%	825
Remaining individualsnot grpmax-eligible	0.0768%	1,302
Middle Eastern	0.0331%	3,021
African / African-American	0.0187%	5,361
South Asian	0.011%	9,109
Finnishnot grpmax-eligible	0.00313%	31,983
East Asian	0.00223%	44,868

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.Phe93=
Coding: c.279C>T
MANE Select: NM_005068
dbSNP: rs145361258
Type: single nucleotide variant
Location: chr6:100450336 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 93: 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-phe93 (accessed [today's date]).

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