Is SETD1A p.Arg461Cys (c.1381C>T) pathogenic?

SETD1A p.Arg461Cys (c.1381C>T) is classified Uncertain significance in SETD1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1768); Ultra-rare (popmax 0.0329%, mid); Associated with epilepsy, early-onset, with or without developmental delay.

What condition is associated with SETD1A p.Arg461Cys (c.1381C>T)?

SETD1A p.Arg461Cys (c.1381C>T) is associated with epilepsy, early-onset, with or without developmental delay (ClinVar).

How common is SETD1A p.Arg461Cys (c.1381C>T) in the general population?

SETD1A p.Arg461Cys (c.1381C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about SETD1A p.Arg461Cys (c.1381C>T)?

AlphaMissense predicts likely benign (score 0.1768) — an in-silico prediction, not a clinical call.

SETD1A p.Arg461Cys

c.1381C>T · rs377325319 · VCV2404727

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epilepsy, early-onset, with or without developmental delay

Computational evidence

Protein change
AlphaMissense	0.1768	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -8.20	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 4.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,694 bp · p 0.44 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00589% 95/1,612,058 alleles · ultra-rare exomes 88/1,459,846 · genomes 7/152,212 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
European (non-Finnish)	0.00703%	14,216
African / African-American	0.00667%	14,988
South Asian	0.00329%	30,360
East Asian	0.00223%	44,872
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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: SETD1A
Protein: p.Arg461Cys
Coding: c.1381C>T
MANE Select: NM_014712
dbSNP: rs377325319
Type: single nucleotide variant
Location: chr16:30965123 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 461: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, early-onset, with or without developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A p.Arg461Gly Uncertain significance ★ ⚠ same residue
SETD1A p.Arg461Ser Uncertain significance ★ ⚠ same residue
SETD1A p.Arg668Ter Pathogenic ★★ same condition
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same condition
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg1392His Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg311Pro 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/setd1a-p-arg461cys (accessed [today's date]).

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