Is SETD5 p.Arg978Trp (c.2932C>T) pathogenic?

SETD5 p.Arg978Trp (c.2932C>T) is classified Likely benign in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.7001); Ultra-rare (popmax 0.0245%, eas).

How common is SETD5 p.Arg978Trp (c.2932C>T) in the general population?

SETD5 p.Arg978Trp (c.2932C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about SETD5 p.Arg978Trp (c.2932C>T)?

AlphaMissense predicts likely pathogenic (score 0.7001) — an in-silico prediction, not a clinical call.

SETD5 p.Arg978Trp

c.2932C>T · rs532266433 · VCV1357522

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7001	likely pathogenic
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -9.74	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 6.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	28.6	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 0.0245% East Asian · 11/44,882 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00173% 28/1,613,842 alleles · ultra-rare exomes 24/1,461,706 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,822
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	29,996
South Asian	0.00329%	30,362
Finnishnot grpmax-eligible	0.00156%	64,020
European (non-Finnish)	0.000509%	196,646

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.Arg978Trp
Coding: c.2932C>T
MANE Select: NM_001080517
dbSNP: rs532266433
Type: single nucleotide variant
Location: chr3:9470666 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 978: 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.Arg978Gln Uncertain significance ★ ⚠ same residue
SETD5 p.Arg978= Likely benign ★ 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-arg978trp (accessed [today's date]).

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