Is SIM1 p.Pro30Ser (c.88C>T) pathogenic?

SIM1 p.Pro30Ser (c.88C>T) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-23). AlphaMissense: likely pathogenic (0.9976); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SIM1 p.Pro30Ser (c.88C>T)?

SIM1 p.Pro30Ser (c.88C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SIM1 p.Pro30Ser (c.88C>T) in the general population?

SIM1 p.Pro30Ser (c.88C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SIM1 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

SIM1 p.Pro30Ser

c.88C>T · VCV4840227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic
REVEL	0.556	indeterminate
SaProt	LLR -12.66	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	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

Grpmax group 0.00167% Admixed American · 1/60,018 alleles

Overall 6.2e-05% 1/1,613,968 alleles · very rare exomes 1/1,461,772 · genomes 0/152,196 · joint denominator

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.Pro30Ser
Coding: c.88C>T
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100463381 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 30: the bhlh domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Pro30Ala Uncertain significance ★ ⚠ same residue
SIM1 p.Pro30= Likely benign same residue
SIM1 p.Cys434Ter Pathogenic ★★ same condition
SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same condition
SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same condition
SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu552Lys Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu617Lys 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-pro30ser (accessed [today's date]).

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