Is SIM1 p.Val151Gly (c.452T>G) pathogenic?

SIM1 p.Val151Gly (c.452T>G) is classified Conflicting classifications of pathogenicity in SIM1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-29). AlphaMissense: ambiguous (0.5351); Ultra-rare (popmax 0.0227%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SIM1 p.Val151Gly (c.452T>G)?

SIM1 p.Val151Gly (c.452T>G) is associated with Inborn genetic diseases (ClinVar).

How common is SIM1 p.Val151Gly (c.452T>G) in the general population?

SIM1 p.Val151Gly (c.452T>G) is ultra-rare (popmax 0.0227%, nfe) (gnomAD).

What do computational predictors say about SIM1 p.Val151Gly (c.452T>G)?

AlphaMissense predicts ambiguous (score 0.5351) — an in-silico prediction, not a clinical call.

SIM1 p.Val151Gly

c.452T>G · rs376356150 · VCV3040180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5351	ambiguous
REVEL	0.495	indeterminate
SaProt	LLR -6.38	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.75, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,473 bp · p 0.74 · regional, not allelic
Overall
CADD	26.6	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 0.0227% European (non-Finnish) · 268/1,179,500 alleles

Filtering AF 0.0205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0179% 289/1,613,444 alleles · ultra-rare exomes 269/1,461,246 · genomes 20/152,198 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0256%	3,904
European (non-Finnish)grpmax	0.0227%	4,401
African / African-American	0.00667%	14,982

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val151Gly
Coding: c.452T>G
MANE Select: NM_005068
dbSNP: rs376356150
Type: single nucleotide variant
Location: chr6:100449596 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIM1 p.Val151= Likely benign same residue
SIM1 p.Cys434Ter Pathogenic ★★ same condition
SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same condition
SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same condition
SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu552Lys Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu617Lys Uncertain significance ★★ ⚠ same condition
SIM1 p.Glu725Lys 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-val151gly (accessed [today's date]).

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