Is SETD5 p.Pro424Ser (c.1270C>T) pathogenic?

SETD5 p.Pro424Ser (c.1270C>T) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-26). AlphaMissense: likely benign (0.0757); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Pro424Ser (c.1270C>T)?

SETD5 p.Pro424Ser (c.1270C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Pro424Ser (c.1270C>T) in the general population?

SETD5 p.Pro424Ser (c.1270C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD5 p.Pro424Ser (c.1270C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

SETD5 p.Pro424Ser

c.1270C>T · rs2041780895 · VCV2473815

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	24.6	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

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.Pro424Ser
Coding: c.1270C>T
MANE Select: NM_001080517
dbSNP: rs2041780895
Type: single nucleotide variant
Location: chr3:9445130 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 424: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.Pro424= Benign/Likely benign ★★ same residue
SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 p.Arg1001Ter Pathogenic ★★ same condition
SETD5 p.Arg308Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Arg361Ter Pathogenic ★★ same condition
SETD5 p.Gln1101Ter Pathogenic ★★ same condition
SETD5 p.Ser668Ter Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Ala1112Ser 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/setd5-p-pro424ser (accessed [today's date]).

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