Is SETD1A p.Ala561Pro (c.1681G>C) pathogenic?

SETD1A p.Ala561Pro (c.1681G>C) is classified Conflicting classifications of pathogenicity in SETD1A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.0931); Ultra-rare (popmax 0.0496%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Ala561Pro (c.1681G>C)?

SETD1A p.Ala561Pro (c.1681G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Ala561Pro (c.1681G>C) in the general population?

SETD1A p.Ala561Pro (c.1681G>C) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about SETD1A p.Ala561Pro (c.1681G>C)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

SETD1A p.Ala561Pro

c.1681G>C · rs373652892 · VCV2407524

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -6.31	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 0.91	GERP -3.6, phastCons 0.79
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	16.88	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 0.0496% Middle Eastern · 3/6,044 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00817%

Overall 0.00168% 27/1,603,580 alleles · ultra-rare exomes 19/1,451,918 · genomes 8/151,662 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,015
African / African-American	0.0175%	5,730
Remaining individualsnot grpmax-eligible	0.00646%	15,476
Admixed American	0.00336%	29,792
European (non-Finnish)	0.000427%	234,446

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.Ala561Pro
Coding: c.1681G>C
MANE Select: NM_014712
dbSNP: rs373652892
Type: single nucleotide variant
Location: chr16:30965423 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 561: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A p.Ala671Thr Uncertain significance ★★ ⚠ same condition
SETD1A p.Ala840Val Uncertain significance ★★ ⚠ same condition
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-ala561pro (accessed [today's date]).

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