Is SETD5 p.Pro176Ala (c.526C>G) pathogenic?

SETD5 p.Pro176Ala (c.526C>G) is classified Likely benign in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.0698); Ultra-rare (popmax 0.0134%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Pro176Ala (c.526C>G)?

SETD5 p.Pro176Ala (c.526C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Pro176Ala (c.526C>G) in the general population?

SETD5 p.Pro176Ala (c.526C>G) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Pro176Ala (c.526C>G)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

SETD5 p.Pro176Ala

c.526C>G · rs781711203 · VCV1375803

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.09	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.0134% African / African-American · 10/74,426 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00553%

Overall 0.000626% 10/1,596,886 alleles · ultra-rare exomes 3/1,444,916 · genomes 7/151,970 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETD5
Protein: p.Pro176Ala
Coding: c.526C>G
MANE Select: NM_001080517
dbSNP: rs781711203
Type: single nucleotide variant
Location: chr3:9435865 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 176: 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.Pro176Leu Uncertain significance ★ ⚠ 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-pro176ala (accessed [today's date]).

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