Is SIM1 p.Leu498= (c.1492C>T) pathogenic?

SIM1 p.Leu498= (c.1492C>T) is classified Likely benign in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-12-15). Ultra-rare (popmax 0.0187%, afr); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Leu498= (c.1492C>T)?

SIM1 p.Leu498= (c.1492C>T) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Leu498= (c.1492C>T) in the general population?

SIM1 p.Leu498= (c.1492C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

SIM1 p.Leu498=

c.1492C>T · rs200610367 · VCV3058253

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

SIM1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3	GERP 1.3, phastCons 1
Overall
CADD	7.457	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,942 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00143% 23/1,609,830 alleles · ultra-rare exomes 19/1,457,508 · genomes 4/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,353
Middle Eastern	0.0165%	6,044
Remaining individualsnot grpmax-eligible	0.0129%	7,781

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.Leu498=
Coding: c.1492C>T
MANE Select: NM_005068
dbSNP: rs200610367
Type: single nucleotide variant
Location: chr6:100393565 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 498: the single-minded c-terminal domain

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

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser199Cys Uncertain significance ★★ same condition
SIM1 p.Gly480Ter Likely pathogenic ★ same condition
SIM1 c.-468+6T>A Uncertain significance ★ same condition
SIM1 p.Ala484Ser Uncertain significance ★ ⚠ same condition
SIM1 p.Asn608Asp Uncertain significance ★ ⚠ same condition
SIM1 p.Lys287Arg Uncertain significance ★ ⚠ same condition
SIM1 p.Pro30Ala 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-leu498 (accessed [today's date]).

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