Is SETD5 p.Arg348Leu (c.1043G>T) pathogenic?

SETD5 p.Arg348Leu (c.1043G>T) is classified Likely pathogenic in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-07). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1.

How common is SETD5 p.Arg348Leu (c.1043G>T) in the general population?

SETD5 p.Arg348Leu (c.1043G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD5 p.Arg348Leu (c.1043G>T)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

SETD5 p.Arg348Leu

c.1043G>T · rs2125194268 · VCV1065941

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic ✓ concordant with ClinVar · top 3% in SETD5
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -15.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETD5
Protein: p.Arg348Leu
Coding: c.1043G>T
MANE Select: NM_001080517
dbSNP: rs2125194268
Type: single nucleotide variant
Location: chr3:9442211 (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

Similar variants

SETD5 p.Arg348Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 p.Arg348Pro Uncertain significance ★ ⚠ same residue
SETD5 p.Arg348Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ same type

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-arg348leu (accessed [today's date]).

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