Is SETD1A p.Pro653Thr (c.1957C>A) pathogenic?

SETD1A p.Pro653Thr (c.1957C>A) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-15). AlphaMissense: ambiguous (0.3432); Very rare (popmax 6.22e-05%); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Pro653Thr (c.1957C>A)?

SETD1A p.Pro653Thr (c.1957C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Pro653Thr (c.1957C>A) in the general population?

SETD1A p.Pro653Thr (c.1957C>A) is very rare (popmax 6.22e-05%) (gnomAD).

What do computational predictors say about SETD1A p.Pro653Thr (c.1957C>A)?

AlphaMissense predicts ambiguous (score 0.3432) — an in-silico prediction, not a clinical call.

SETD1A p.Pro653Thr

c.1957C>A · VCV4864334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.22e-05%)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3432	ambiguous
REVEL	0.314	indeterminate
SaProt	LLR -10.98	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	24.2	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 6.22e-05%

Overall 6.22e-05% 1/1,608,104 alleles · very rare exomes 0/1,456,802 · genomes 1/151,302 · joint denominator

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.Pro653Thr
Coding: c.1957C>A
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30965838 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 653: 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.Pro653Ala Uncertain significance ★ ⚠ same residue
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

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-pro653thr (accessed [today's date]).

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