Is SETD5 p.Ala232Val (c.695C>T) pathogenic?

SETD5 p.Ala232Val (c.695C>T) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). AlphaMissense: likely benign (0.1046); Ultra-rare (popmax 0.0329%, mid); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Ala232Val (c.695C>T) in the general population?

SETD5 p.Ala232Val (c.695C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about SETD5 p.Ala232Val (c.695C>T)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

SETD5 p.Ala232Val

Q: What condition is associated with SETD5 p.Ala232Val (c.695C>T)?

SETD5 p.Ala232Val (c.695C>T) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.695C>T · VCV3391243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -5.66	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 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	24.5	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00155% 25/1,613,834 alleles · ultra-rare exomes 23/1,461,658 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.00769%	13,012
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)	0.000932%	107,261

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: SETD5
Protein: p.Ala232Val
Coding: c.695C>T
MANE Select: NM_001080517
Type: single nucleotide variant
Location: chr3:9440583 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.Ala232Thr Uncertain significance ★★ ⚠ same residue
SETD5 p.Ala232= Likely benign ★ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same condition
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same condition
SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 c.3631+1G>A Pathogenic ★★ same condition
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg1001Ter Pathogenic ★★ 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/setd5-p-ala232val (accessed [today's date]).

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