Is SIM1 p.Asp707His (c.2119G>C) pathogenic?

SIM1 p.Asp707His (c.2119G>C) is classified Conflicting classifications of pathogenicity in SIM1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2024-10-30). AlphaMissense: likely pathogenic (0.6587); Rare (popmax 0.14%, nfe); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Asp707His (c.2119G>C)?

SIM1 p.Asp707His (c.2119G>C) is associated with obesity due to SIM1 deficiency, Moebius syndrome, monogenic diabetes (ClinVar).

How common is SIM1 p.Asp707His (c.2119G>C) in the general population?

SIM1 p.Asp707His (c.2119G>C) is rare (popmax 0.14%, nfe) (gnomAD).

What do computational predictors say about SIM1 p.Asp707His (c.2119G>C)?

AlphaMissense predicts likely pathogenic (score 0.6587) — an in-silico prediction, not a clinical call.

SIM1 p.Asp707His

c.2119G>C · rs74726213 · VCV254101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6587 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.14%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
AlphaMissense	0.6587	likely pathogenic
REVEL	0.376	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.14% European (non-Finnish) · 1,657/1,180,030 alleles

Filtering AF 0.135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.109% 1,767/1,614,118 alleles · rare exomes 1,681/1,461,874 · genomes 86/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.14%	712
Remaining individualsnot grpmax-eligible	0.101%	992
Admixed American	0.04%	2,501
Middle Eastern	0.033%	3,031
African / African-American	0.024%	4,168
Finnishnot grpmax-eligible	0.00469%	21,342

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.Asp707His
Coding: c.2119G>C
MANE Select: NM_005068
dbSNP: rs74726213
Type: single nucleotide variant
Location: chr6:100390543 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 707: 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

Also linked: Moebius syndrome monogenic diabetes

Similar variants

SIM1 p.Arg550His Uncertain significance ★★ ⚠ same condition
SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same condition
SIM1 p.His632Tyr 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

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-asp707his (accessed [today's date]).

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