Is SIM1 p.Val208= (c.624G>A) pathogenic?

SIM1 p.Val208= (c.624G>A) is classified Conflicting classifications of pathogenicity in SIM1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-24). Ultra-rare (popmax 0.033%, mid); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Val208= (c.624G>A)?

SIM1 p.Val208= (c.624G>A) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Val208= (c.624G>A) in the general population?

SIM1 p.Val208= (c.624G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

SIM1 p.Val208=

c.624G>A · rs753737612 · VCV436727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 0.81	GERP -2.2, phastCons 1
Overall
CADD	11.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00539% 87/1,614,108 alleles · ultra-rare exomes 81/1,461,826 · genomes 6/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
European (non-Finnish)	0.00644%	15,527
Admixed American	0.005%	20,011
Remaining individualsnot grpmax-eligible	0.0048%	20,836
South Asian	0.0022%	45,537
African / African-American	0.00133%	75,048

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.Val208=
Coding: c.624G>A
MANE Select: NM_005068
dbSNP: rs753737612
Type: single nucleotide variant
Location: chr6:100448598 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70

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-val208 (accessed [today's date]).

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