Is SIM1 p.Met102Ile (c.306G>A) pathogenic?

SIM1 p.Met102Ile (c.306G>A) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely pathogenic (0.9493); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SIM1 p.Met102Ile (c.306G>A)?

SIM1 p.Met102Ile (c.306G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SIM1 p.Met102Ile (c.306G>A) in the general population?

SIM1 p.Met102Ile (c.306G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about SIM1 p.Met102Ile (c.306G>A)?

AlphaMissense predicts likely pathogenic (score 0.9493) — an in-silico prediction, not a clinical call.

SIM1 p.Met102Ile

c.306G>A · rs748261326 · VCV2473395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9493 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9493	likely pathogenic
REVEL	0.328	indeterminate
SaProt	LLR -10.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0223% East Asian · 10/44,876 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.000867% 14/1,614,004 alleles · ultra-rare exomes 12/1,461,828 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,488
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Met102Ile
Coding: c.306G>A
MANE Select: NM_005068
dbSNP: rs748261326
Type: single nucleotide variant
Location: chr6:100450309 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 102: the pas 1 domain

Full SIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Cys434Ter Pathogenic ★★ same condition
SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same condition
SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same condition
SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu552Lys Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu617Lys Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu725Lys Uncertain significance ★★ same condition
SIM1 p.Gly203Cys Uncertain significance ★★ ⚠ 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-met102ile (accessed [today's date]).

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