Is SIM1 p.Arg657Pro (c.1970G>C) pathogenic?

SIM1 p.Arg657Pro (c.1970G>C) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3775); Very rare (popmax 0.00446%, eas).

How common is SIM1 p.Arg657Pro (c.1970G>C) in the general population?

SIM1 p.Arg657Pro (c.1970G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about SIM1 p.Arg657Pro (c.1970G>C)?

AlphaMissense predicts ambiguous (score 0.3775) — an in-silico prediction, not a clinical call.

SIM1 p.Arg657Pro

c.1970G>C · VCV4724292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.3775	ambiguous
REVEL	0.326	indeterminate
SaProt	LLR -5.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	25.6	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,934 alleles · very rare exomes 1/1,461,880 · genomes 1/152,054 · 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.Arg657Pro
Coding: c.1970G>C
MANE Select: NM_005068
Type: single nucleotide variant
Location: chr6:100390692 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 657: the single-minded c-terminal domain

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

Similar variants

SIM1 p.Arg657Trp Uncertain significance ★ ⚠ same residue
SIM1 p.Arg657Gln Uncertain significance ⚠ same residue
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

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-arg657pro (accessed [today's date]).

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