Is SETD5 p.Ala388Pro (c.1162G>C) pathogenic?

SETD5 p.Ala388Pro (c.1162G>C) is classified Likely benign in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.6438); Ultra-rare (popmax 0.0447%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Ala388Pro (c.1162G>C)?

SETD5 p.Ala388Pro (c.1162G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD5 p.Ala388Pro (c.1162G>C) in the general population?

SETD5 p.Ala388Pro (c.1162G>C) is ultra-rare (popmax 0.0447%, afr) (gnomAD).

What do computational predictors say about SETD5 p.Ala388Pro (c.1162G>C)?

AlphaMissense predicts likely pathogenic (score 0.6438) — an in-silico prediction, not a clinical call.

SETD5 p.Ala388Pro

c.1162G>C · rs200900982 · VCV2174255

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0447%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6438	likely pathogenic
REVEL	0.532	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 2,937 bp · p 5e-10 · 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

Grpmax group 0.0447% African / African-American · 31/69,276 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00233% 34/1,461,172 alleles · ultra-rare exomes 19/1,308,984 · genomes 15/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0447%	2,235
Admixed American	0.00273%	36,578
Remaining individualsnot grpmax-eligible	0.00179%	55,854
European (non-Finnish)	9.06e-05%	1,103,418

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.Ala388Pro
Coding: c.1162G>C
MANE Select: NM_001080517
dbSNP: rs200900982
Type: single nucleotide variant
Location: chr3:9443392 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 388: the set domain

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.Ala388Val 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-ala388pro (accessed [today's date]).

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