Is SETD5 p.Ala1049Pro (c.3145G>C) pathogenic?

SETD5 p.Ala1049Pro (c.3145G>C) is classified Uncertain significance in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely benign (0.0834); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Ala1049Pro (c.3145G>C)?

SETD5 p.Ala1049Pro (c.3145G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Ala1049Pro (c.3145G>C) in the general population?

SETD5 p.Ala1049Pro (c.3145G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD5 p.Ala1049Pro (c.3145G>C)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

SETD5 p.Ala1049Pro

c.3145G>C · VCV3794658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0834 · 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	0.0834	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.62	GERP -1.9, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	16.64	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.Ala1049Pro
Coding: c.3145G>C
MANE Select: NM_001080517
Type: single nucleotide variant
Location: chr3:9470879 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1049: a UniProt-annotated variant site (in mrd23); the 'disordered' region

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.Ala1049Gly Uncertain significance ★ ⚠ same residue
SETD5 p.Ala1049Thr 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

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-ala1049pro (accessed [today's date]).

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