Is SETD1A p.Pro773Leu (c.2318C>T) pathogenic?

SETD1A p.Pro773Leu (c.2318C>T) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-27). AlphaMissense: likely benign (0.1196); Very rare (popmax 0.00017%, nfe).

How common is SETD1A p.Pro773Leu (c.2318C>T) in the general population?

SETD1A p.Pro773Leu (c.2318C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Pro773Leu (c.2318C>T)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

SETD1A p.Pro773Leu

c.2318C>T · VCV3893650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.41, phastCons 0.97
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	18.25	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 0.00017% European (non-Finnish) · 2/1,179,694 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,970 alleles · very rare exomes 2/1,460,634 · genomes 0/152,336 · 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.Pro773Leu
Coding: c.2318C>T
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30966199 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 773: a UniProt-annotated variant site (in nedsid)

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

Similar variants

SETD1A p.Pro773= Likely benign ★ same residue
SETD1A c.518-2A>G Pathogenic ★★ same type
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg668Ter Pathogenic ★★ same type
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same type
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Tyr646Ter Pathogenic ★★ same type

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-pro773leu (accessed [today's date]).

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