Is SIM1 p.Ser5Pro (c.13T>C) pathogenic?

SIM1 p.Ser5Pro (c.13T>C) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-14). AlphaMissense: likely pathogenic (0.9964); Absent from gnomAD v4.1.

How common is SIM1 p.Ser5Pro (c.13T>C) in the general population?

SIM1 p.Ser5Pro (c.13T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIM1 p.Ser5Pro (c.13T>C)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

SIM1 p.Ser5Pro

c.13T>C · rs2482182450 · VCV2663718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic
REVEL	0.422	indeterminate
SaProt	LLR -14.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIM1
Protein: p.Ser5Pro
Coding: c.13T>C
MANE Select: NM_005068
dbSNP: rs2482182450
Type: single nucleotide variant
Location: chr6:100463456 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 5: 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-ser5pro (accessed [today's date]).

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