Is SETD1A p.Pro414Thr (c.1240C>A) pathogenic?

SETD1A p.Pro414Thr (c.1240C>A) is classified Uncertain significance in SETD1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-01). AlphaMissense: ambiguous (0.3404); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Pro414Thr (c.1240C>A)?

SETD1A p.Pro414Thr (c.1240C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Pro414Thr (c.1240C>A) in the general population?

SETD1A p.Pro414Thr (c.1240C>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about SETD1A p.Pro414Thr (c.1240C>A)?

AlphaMissense predicts ambiguous (score 0.3404) — an in-silico prediction, not a clinical call.

SETD1A p.Pro414Thr

c.1240C>A · rs781251172 · VCV2401962

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3404	ambiguous
REVEL	0.308	indeterminate
SaProt	LLR -8.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,694 bp · p 0.44 · regional, not allelic
Overall
CADD	19.18	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 0.00833% Admixed American · 5/59,992 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000992% 16/1,613,640 alleles · very rare exomes 11/1,461,444 · genomes 5/152,196 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,998
Remaining individualsnot grpmax-eligible	0.0048%	20,827
South Asian	0.0022%	45,529
European (non-Finnish)	0.000509%	196,649

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.Pro414Thr
Coding: c.1240C>A
MANE Select: NM_014712
dbSNP: rs781251172
Type: single nucleotide variant
Location: chr16:30964982 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 414: 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-pro414thr (accessed [today's date]).

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