Is SETD5 p.Arg409Gln (c.1226G>A) pathogenic?

SETD5 p.Arg409Gln (c.1226G>A) is classified Likely benign in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-07). AlphaMissense: likely benign (0.139); Ultra-rare (popmax 0.02%, amr).

How common is SETD5 p.Arg409Gln (c.1226G>A) in the general population?

SETD5 p.Arg409Gln (c.1226G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about SETD5 p.Arg409Gln (c.1226G>A)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

SETD5 p.Arg409Gln

c.1226G>A · rs200411830 · VCV1350367

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 2,937 bp · p 5e-10 · regional, not allelic
Overall
CADD	27.2	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 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00291% 47/1,613,762 alleles · ultra-rare exomes 42/1,461,568 · genomes 5/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
South Asian	0.00549%	18,211
East Asian	0.00446%	22,437
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,572
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-American	0.00267%	37,493
European (non-Finnish)	0.00195%	51,296

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.Arg409Gln
Coding: c.1226G>A
MANE Select: NM_001080517
dbSNP: rs200411830
Type: single nucleotide variant
Location: chr3:9445086 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 409: 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.Arg409Gly Uncertain significance ★★ ⚠ 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
SETD5 p.Arg1001Ter 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-arg409gln (accessed [today's date]).

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