Is SIM1 p.Arg69Gly (c.205C>G) pathogenic?

SIM1 p.Arg69Gly (c.205C>G) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-09). AlphaMissense: likely benign (0.3047); Absent from gnomAD v4.1.

How common is SIM1 p.Arg69Gly (c.205C>G) in the general population?

SIM1 p.Arg69Gly (c.205C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIM1 p.Arg69Gly (c.205C>G)?

AlphaMissense predicts likely benign (score 0.3047) — an in-silico prediction, not a clinical call.

SIM1 p.Arg69Gly

c.205C>G · rs1398673847 · VCV1305639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3047 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3047	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -12.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.5	GERP -1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	21.7	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

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.Arg69Gly
Coding: c.205C>G
MANE Select: NM_005068
dbSNP: rs1398673847
Type: single nucleotide variant
Location: chr6:100453815 (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

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-arg69gly (accessed [today's date]).

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