Is SIM1 p.Thr712Ile (c.2135C>T) pathogenic?

SIM1 p.Thr712Ile (c.2135C>T) is classified Uncertain significance in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-06). AlphaMissense: ambiguous (0.3459); Ultra-rare (popmax 0.0158%, nfe); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Thr712Ile (c.2135C>T)?

SIM1 p.Thr712Ile (c.2135C>T) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Thr712Ile (c.2135C>T) in the general population?

SIM1 p.Thr712Ile (c.2135C>T) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about SIM1 p.Thr712Ile (c.2135C>T)?

AlphaMissense predicts ambiguous (score 0.3459) — an in-silico prediction, not a clinical call.

SIM1 p.Thr712Ile

c.2135C>T · rs745821604 · VCV2633120

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3459 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

SIM1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3459	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic
Overall
CADD	25.1	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 0.0158% European (non-Finnish) · 187/1,180,036 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0123% 199/1,614,080 alleles · ultra-rare exomes 188/1,461,888 · genomes 11/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0158%	6,310
African / African-American	0.00667%	14,983
Remaining individualsnot grpmax-eligible	0.0064%	15,623
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,544

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.Thr712Ile
Coding: c.2135C>T
MANE Select: NM_005068
dbSNP: rs745821604
Type: single nucleotide variant
Location: chr6:100390527 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 712: the single-minded c-terminal domain

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

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser199Cys Uncertain significance ★★ same condition
SIM1 p.Gly480Ter Likely pathogenic ★ same condition
SIM1 c.-468+6T>A Uncertain significance ★ same condition
SIM1 p.Ala484Ser Uncertain significance ★ ⚠ same condition
SIM1 p.Asn608Asp Uncertain significance ★ ⚠ same condition
SIM1 p.Lys287Arg Uncertain significance ★ ⚠ same condition
SIM1 p.Pro30Ala 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-thr712ile (accessed [today's date]).

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