Is SIM1 p.Ser41Tyr (c.122C>A) pathogenic?

SIM1 p.Ser41Tyr (c.122C>A) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.9999); No allele count reported in gnomAD v4.1 (AN 1,614,032).

How common is SIM1 p.Ser41Tyr (c.122C>A) in the general population?

SIM1 p.Ser41Tyr (c.122C>A) is no allele count reported in gnomAD v4.1 (AN 1,614,032) (gnomAD).

What do computational predictors say about SIM1 p.Ser41Tyr (c.122C>A)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

SIM1 p.Ser41Tyr

c.122C>A · VCV4082862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,032)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 5% in SIM1
REVEL	0.732	pathogenic-leaning
SaProt	LLR -13.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	33.0	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

No allele count reported in gnomAD v4.1 (AN 1,614,032). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SIM1
Protein: p.Ser41Tyr
Coding: c.122C>A
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100463347 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 41: the bhlh domain

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

Similar variants

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
SIM1 p.Glu552Lys 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-ser41tyr (accessed [today's date]).

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