Is SIM1 p.Ser622Pro (c.1864T>C) pathogenic?

SIM1 p.Ser622Pro (c.1864T>C) is classified Likely benign in SIM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0514); Rare (popmax 0.289%, afr); Associated with monogenic diabetes.

What condition is associated with SIM1 p.Ser622Pro (c.1864T>C)?

SIM1 p.Ser622Pro (c.1864T>C) is associated with monogenic diabetes (ClinVar).

How common is SIM1 p.Ser622Pro (c.1864T>C) in the general population?

SIM1 p.Ser622Pro (c.1864T>C) is rare (popmax 0.289%, afr) (gnomAD).

What do computational predictors say about SIM1 p.Ser622Pro (c.1864T>C)?

AlphaMissense predicts likely benign (score 0.0514) — an in-silico prediction, not a clinical call.

SIM1 p.Ser622Pro

c.1864T>C · rs141415931 · VCV756451

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0514 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.289%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.0514	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.99	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 1.8	GERP 0.029, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	9.888	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 0.289% African / African-American · 217/75,002 alleles

Filtering AF 0.258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.246%

Overall 0.0146% 235/1,614,080 alleles · rare exomes 86/1,461,878 · genomes 149/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.289%	346
Admixed American	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0096%	10,418

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.Ser622Pro
Coding: c.1864T>C
MANE Select: NM_005068
dbSNP: rs141415931
Type: single nucleotide variant
Location: chr6:100390798 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 622: 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.Ser622Phe Uncertain significance ★★ ⚠ same residue
SIM1 p.Arg550His Uncertain significance ★★ ⚠ same condition
SIM1 p.His632Tyr Uncertain significance ★★ ⚠ same condition
SIM1 p.Arg703Trp Uncertain significance ★ ⚠ 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-ser622pro (accessed [today's date]).

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