Is SIM1 p.Arg665His (c.1994G>A) pathogenic?

SIM1 p.Arg665His (c.1994G>A) is classified Benign in SIM1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.0753); Low-frequency (popmax 3.76%, amr); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Arg665His (c.1994G>A)?

SIM1 p.Arg665His (c.1994G>A) is associated with obesity due to SIM1 deficiency, Moebius syndrome (ClinVar).

How common is SIM1 p.Arg665His (c.1994G>A) in the general population?

SIM1 p.Arg665His (c.1994G>A) is low-frequency (popmax 3.76%, amr) (gnomAD).

What do computational predictors say about SIM1 p.Arg665His (c.1994G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

SIM1 p.Arg665His

c.1994G>A · rs146866401 · VCV254102

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.76%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 3.76% Admixed American · 2,257/60,002 alleles

Filtering AF 3.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.58%

Overall 0.169% 2,734/1,614,098 alleles · low-frequency exomes 2,313/1,461,882 · genomes 421/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	3.76%	27
East Asian	0.691%	145
Remaining individualsnot grpmax-eligible	0.139%	718
African / African-American	0.0307%	3,262
South Asian	0.0242%	4,140
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00288%	34,706

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.Arg665His
Coding: c.1994G>A
MANE Select: NM_005068
dbSNP: rs146866401
Type: single nucleotide variant
Location: chr6:100390668 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 665: 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

Similar variants

SIM1 p.Arg665Cys Uncertain significance ★ ⚠ same residue
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

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-arg665his (accessed [today's date]).

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