Is SIM1 p.Glu62Lys (c.184G>A) pathogenic?

SIM1 p.Glu62Lys (c.184G>A) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-01-21). AlphaMissense: likely pathogenic (0.9088); Ultra-rare (popmax 0.0101%, amr).

How common is SIM1 p.Glu62Lys (c.184G>A) in the general population?

SIM1 p.Glu62Lys (c.184G>A) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

What do computational predictors say about SIM1 p.Glu62Lys (c.184G>A)?

AlphaMissense predicts likely pathogenic (score 0.9088) — an in-silico prediction, not a clinical call.

SIM1 p.Glu62Lys

c.184G>A · VCV3358099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9088 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9088	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -10.40	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	29.7	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 0.0101% Admixed American · 6/59,670 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000869% 14/1,611,302 alleles · ultra-rare exomes 10/1,459,120 · genomes 4/152,182 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,945
Remaining individualsnot grpmax-eligible	0.0016%	62,378
European (non-Finnish)	0.000594%	168,406

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.Glu62Lys
Coding: c.184G>A
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100453836 (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

Similar variants

SIM1 p.Glu62Gly Uncertain significance ★ ⚠ same residue
SIM1 p.Cys434Ter Pathogenic ★★ same type
SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same type
SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same type
SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same type
SIM1 p.Arg550His Uncertain significance ★★ ⚠ same type
SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same type
SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same type

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-glu62lys (accessed [today's date]).

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