Is SIM1 p.Arg703Trp (c.2107C>T) pathogenic?

SIM1 p.Arg703Trp (c.2107C>T) is classified Uncertain significance in SIM1 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-10-12). AlphaMissense: likely benign (0.271); Ultra-rare (popmax 0.0333%, afr); Associated with monogenic diabetes.

What condition is associated with SIM1 p.Arg703Trp (c.2107C>T)?

SIM1 p.Arg703Trp (c.2107C>T) is associated with monogenic diabetes (ClinVar).

How common is SIM1 p.Arg703Trp (c.2107C>T) in the general population?

SIM1 p.Arg703Trp (c.2107C>T) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about SIM1 p.Arg703Trp (c.2107C>T)?

AlphaMissense predicts likely benign (score 0.271) — an in-silico prediction, not a clinical call.

SIM1 p.Arg703Trp

c.2107C>T · rs532142781 · VCV917477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.271 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.271	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0333% African / African-American · 25/75,042 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00316% 51/1,614,122 alleles · ultra-rare exomes 25/1,461,868 · genomes 26/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,002
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00625%	16,005
Admixed American	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.00153%	65,556

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.Arg703Trp
Coding: c.2107C>T
MANE Select: NM_005068
dbSNP: rs532142781
Type: single nucleotide variant
Location: chr6:100390555 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 703: the single-minded c-terminal domain

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

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Arg703Gln Uncertain significance ★ ⚠ same residue
SIM1 p.Arg550His Uncertain significance ★★ ⚠ same condition
SIM1 p.His632Tyr Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser622Pro Likely benign ★★ same condition
SIM1 p.Asp707His Conflicting classifications of pathogenicity ★ ⚠ same condition
SIM1 p.Ile128Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
SIM1 p.Met574Val Conflicting classifications of pathogenicity ★ ⚠ same condition
SIM1 p.Cys434Ter Pathogenic ★★ 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-arg703trp (accessed [today's date]).

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