Is SETD1B p.Ala732Val (c.2195C>T) pathogenic?

SETD1B p.Ala732Val (c.2195C>T) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). AlphaMissense: likely benign (0.1896); Very rare (popmax 0.00258%, eas); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Ala732Val (c.2195C>T)?

SETD1B p.Ala732Val (c.2195C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Ala732Val (c.2195C>T) in the general population?

SETD1B p.Ala732Val (c.2195C>T) is very rare (popmax 0.00258%, eas) (gnomAD).

What do computational predictors say about SETD1B p.Ala732Val (c.2195C>T)?

AlphaMissense predicts likely benign (score 0.1896) — an in-silico prediction, not a clinical call.

SETD1B p.Ala732Val

c.2195C>T · rs1298829370 · VCV3160610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00258%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1896	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.14	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 3	GERP 0.16, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	13.97	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 0.00258% East Asian · 1/38,748 alleles

Overall 0.000282% 4/1,418,306 alleles · very rare exomes 4/1,277,238 · genomes 0/141,068 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00448%	22,306
East Asiangrpmax	0.00258%	38,748
Finnishnot grpmax-eligible	0.0021%	47,540
European (non-Finnish)	9.24e-05%	1,081,858

Ashkenazi Jewish 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: SETD1B
Protein: p.Ala732Val
Coding: c.2195C>T
MANE Select: NM_001353345
dbSNP: rs1298829370
Type: single nucleotide variant
Location: chr12:121814410 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB

Full SETD1B 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

SETD1B p.Ala732= Likely benign ★ same residue
SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same condition
SETD1B p.Ala654Thr Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1428Trp Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1458His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1643His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1670Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg467Gln 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/setd1b-p-ala732val (accessed [today's date]).

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