Is SETD1A p.Arg1402Pro (c.4205G>C) pathogenic?

SETD1A p.Arg1402Pro (c.4205G>C) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.16); Rare (popmax 0.548%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Arg1402Pro (c.4205G>C)?

SETD1A p.Arg1402Pro (c.4205G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Arg1402Pro (c.4205G>C) in the general population?

SETD1A p.Arg1402Pro (c.4205G>C) is rare (popmax 0.548%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Arg1402Pro (c.4205G>C)?

AlphaMissense predicts likely benign (score 0.16) — an in-silico prediction, not a clinical call.

SETD1A p.Arg1402Pro

c.4205G>C · rs1388876662 · VCV2360131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.16 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.548%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.16	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -5.47	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 4.6	GERP 0.63, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.57 · regional, not allelic
Overall
CADD	14.32	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 0.548% European (non-Finnish) · 5,134/937,198 alleles

Filtering AF 0.535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.53%

Overall 0.466% 5,790/1,242,466 alleles · rare exomes 5,687/1,098,884 · genomes 103/143,582 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.548%	183
Middle Eastern	0.448%	223
Remaining individualsnot grpmax-eligible	0.445%	225
East Asian	0.236%	423
Finnishnot grpmax-eligible	0.214%	467
African / African-American	0.182%	549
Ashkenazi Jewishnot grpmax-eligible	0.16%	625
South Asian	0.154%	647
Amishnot grpmax-eligible	0.116%	862
Admixed American	0.0863%	1,158

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.Arg1402Pro
Coding: c.4205G>C
MANE Select: NM_014712
dbSNP: rs1388876662
Type: single nucleotide variant
Location: chr16:30979991 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1402: the 'disordered' region; a UniProt-annotated variant site (in nedsid)

Full SETD1A 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

SETD1A p.Ala671Thr Uncertain significance ★★ ⚠ same condition
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SETD1A p.Arg1576Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg385His Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1638Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu1009Lys Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu905Lys 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-arg1402pro (accessed [today's date]).

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