Is SETD5 p.Val799Ile (c.2395G>A) pathogenic?

SETD5 p.Val799Ile (c.2395G>A) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.069); Very rare (popmax 0.00224%, eas); Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

How common is SETD5 p.Val799Ile (c.2395G>A) in the general population?

SETD5 p.Val799Ile (c.2395G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about SETD5 p.Val799Ile (c.2395G>A)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

SETD5 p.Val799Ile

Q: What condition is associated with SETD5 p.Val799Ile (c.2395G>A)?

SETD5 p.Val799Ile (c.2395G>A) is associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

c.2395G>A · rs1202232628 · VCV2689951

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.80	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 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	21.3	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 0.00224% East Asian · 1/44,698 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000621% 10/1,609,386 alleles · very rare exomes 10/1,457,094 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,698
South Asian	0.00222%	45,072
European (non-Finnish)	0.000594%	168,379

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.Val799Ile
Coding: c.2395G>A
MANE Select: NM_001080517
dbSNP: rs1202232628
Type: single nucleotide variant
Location: chr3:9453787 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 799: the 'disordered' region; a UniProt-annotated variant site (in mrd23)

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.Val799fs Likely pathogenic ★ 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
SETD5 p.Arg1072Ter Pathogenic/Likely 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-val799ile (accessed [today's date]).

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