Is SETD5 p.Ile128Val (c.382A>G) pathogenic?

SETD5 p.Ile128Val (c.382A>G) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-24). AlphaMissense: likely benign (0.101); Very rare (popmax 0.0088%, sas).

How common is SETD5 p.Ile128Val (c.382A>G) in the general population?

SETD5 p.Ile128Val (c.382A>G) is very rare (popmax 0.0088%, sas) (gnomAD).

What do computational predictors say about SETD5 p.Ile128Val (c.382A>G)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

SETD5 p.Ile128Val

c.382A>G · rs780263494 · VCV235575

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0088%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -5.44	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 9.1	GERP 0.89, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	22.3	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 0.0088% South Asian · 8/90,886 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00105% 17/1,613,312 alleles · very rare exomes 14/1,461,112 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0088%	11,361
African / African-American	0.00401%	24,966
Remaining individualsnot grpmax-eligible	0.0016%	62,454
European (non-Finnish)	0.000424%	235,939

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.Ile128Val
Coding: c.382A>G
MANE Select: NM_001080517
dbSNP: rs780263494
Type: single nucleotide variant
Location: chr3:9434876 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10

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

Similar variants

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
SETD5 p.Arg1001Ter Pathogenic ★★ same type
SETD5 p.Arg1072Ter 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-ile128val (accessed [today's date]).

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