Is SETD5 p.Arg757Pro (c.2270G>C) pathogenic?

SETD5 p.Arg757Pro (c.2270G>C) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-02). AlphaMissense: likely pathogenic (0.991); Absent from gnomAD v4.1.

How common is SETD5 p.Arg757Pro (c.2270G>C) in the general population?

SETD5 p.Arg757Pro (c.2270G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD5 p.Arg757Pro (c.2270G>C)?

AlphaMissense predicts likely pathogenic (score 0.991) — an in-silico prediction, not a clinical call.

SETD5 p.Arg757Pro

c.2270G>C · rs530225114 · VCV1683974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.991	likely pathogenic · top 6% in SETD5
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -4.92	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	30.0	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.Arg757Pro
Coding: c.2270G>C
MANE Select: NM_001080517
dbSNP: rs530225114
Type: single nucleotide variant
Location: chr3:9448554 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 757: a UniProt-annotated variant site (in mrd23)

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

Similar variants

SETD5 p.Arg757Cys Uncertain significance ★ ⚠ same residue
SETD5 p.Arg757fs Pathogenic 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-arg757pro (accessed [today's date]).

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