Is SETD5 p.Arg1426Pro (c.4277G>C) pathogenic?

SETD5 p.Arg1426Pro (c.4277G>C) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: ambiguous (0.5219); Absent from gnomAD v4.1.

How common is SETD5 p.Arg1426Pro (c.4277G>C) in the general population?

SETD5 p.Arg1426Pro (c.4277G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD5 p.Arg1426Pro (c.4277G>C)?

AlphaMissense predicts ambiguous (score 0.5219) — an in-silico prediction, not a clinical call.

SETD5 p.Arg1426Pro

c.4277G>C · rs757364157 · VCV2502660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5219 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5219	ambiguous
REVEL	0.532	indeterminate
SaProt	LLR -5.28	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,020 bp · p 0.14 · regional, not allelic
Overall
CADD	27.0	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.Arg1426Pro
Coding: c.4277G>C
MANE Select: NM_001080517
dbSNP: rs757364157
Type: single nucleotide variant
Location: chr3:9476039 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1426: a UniProt-annotated variant site (in mrd23); the 'disordered' region

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

Similar variants

SETD5 p.Arg1426Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD5 p.Arg1426Ter 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
SETD5 c.960-5C>G Pathogenic/Likely 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-arg1426pro (accessed [today's date]).

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