Is SIM1 p.Ser622Phe (c.1865C>T) pathogenic?

SIM1 p.Ser622Phe (c.1865C>T) is classified Uncertain significance in SIM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0961); Ultra-rare (popmax 0.0567%, amr); Associated with obesity due to SIM1 deficiency.

What condition is associated with SIM1 p.Ser622Phe (c.1865C>T)?

SIM1 p.Ser622Phe (c.1865C>T) is associated with obesity due to SIM1 deficiency (ClinVar).

How common is SIM1 p.Ser622Phe (c.1865C>T) in the general population?

SIM1 p.Ser622Phe (c.1865C>T) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about SIM1 p.Ser622Phe (c.1865C>T)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

SIM1 p.Ser622Phe

c.1865C>T · rs199543656 · VCV904719

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

obesity due to SIM1 deficiency

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.05	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 8.6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0567% Admixed American · 34/60,004 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00967% 156/1,614,044 alleles · ultra-rare exomes 139/1,461,882 · genomes 17/152,162 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
European (non-Finnish)	0.00992%	10,086
Remaining individualsnot grpmax-eligible	0.008%	12,497

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.Ser622Phe
Coding: c.1865C>T
MANE Select: NM_005068
dbSNP: rs199543656
Type: single nucleotide variant
Location: chr6:100390797 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 622: 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.Ser622Pro Likely benign ★★ same residue
SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same condition
SIM1 p.Leu332Phe 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-ser622phe (accessed [today's date]).

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