Is SIM1 p.Ser199Cys (c.596C>G) pathogenic?

SIM1 p.Ser199Cys (c.596C>G) is classified Uncertain significance in SIM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-14). AlphaMissense: ambiguous (0.4098); Ultra-rare (popmax 0.0823%, mid); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Ser199Cys (c.596C>G)?

SIM1 p.Ser199Cys (c.596C>G) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Ser199Cys (c.596C>G) in the general population?

SIM1 p.Ser199Cys (c.596C>G) is ultra-rare (popmax 0.0823%, mid) (gnomAD).

What do computational predictors say about SIM1 p.Ser199Cys (c.596C>G)?

AlphaMissense predicts ambiguous (score 0.4098) — an in-silico prediction, not a clinical call.

SIM1 p.Ser199Cys

c.596C>G · rs781416633 · VCV1391986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0823%, mid)

Conditions

SIM1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4098	ambiguous
REVEL	0.629	indeterminate
SaProt	LLR -10.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,473 bp · p 0.74 · 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 0.0823% Middle Eastern · 5/6,078 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00118% 19/1,613,750 alleles · ultra-rare exomes 17/1,461,548 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0823%	1,216
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00333%	30,005
African / African-American	0.00267%	37,467
European (non-Finnish)	0.000508%	196,673

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.Ser199Cys
Coding: c.596C>G
MANE Select: NM_005068
dbSNP: rs781416633
Type: single nucleotide variant
Location: chr6:100448626 (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

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Ser199= Likely benign same residue
SIM1 p.Arg374Trp 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-ser199cys (accessed [today's date]).

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