Is SETD5 p.Arg348Trp (c.1042C>T) pathogenic?

SETD5 p.Arg348Trp (c.1042C>T) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-04-18). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 8.48e-05%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with SETD5 p.Arg348Trp (c.1042C>T)?

SETD5 p.Arg348Trp (c.1042C>T) is associated with neurodevelopmental disorder, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

How common is SETD5 p.Arg348Trp (c.1042C>T) in the general population?

SETD5 p.Arg348Trp (c.1042C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETD5 p.Arg348Trp (c.1042C>T)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

SETD5 p.Arg348Trp

c.1042C>T · rs1553621798 · VCV450307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in SETD5
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -17.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 2,937 bp · p 5e-10 · regional, not allelic
Overall
CADD	33.0	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 8.48e-05% European (non-Finnish) · 1/1,179,690 alleles

Overall 6.2e-05% 1/1,612,936 alleles · very rare exomes 1/1,460,766 · genomes 0/152,170 · joint denominator

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.Arg348Trp
Coding: c.1042C>T
MANE Select: NM_001080517
dbSNP: rs1553621798
Type: single nucleotide variant
Location: chr3:9442210 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 348: the set domain

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Similar variants

SETD5 p.Arg348Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 p.Arg348Leu Likely pathogenic ★ same residue
SETD5 p.Arg348Pro Uncertain significance ★ ⚠ 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

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-arg348trp (accessed [today's date]).

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