Is SETD1A p.Pro1318Leu (c.3953C>T) pathogenic?

SETD1A p.Pro1318Leu (c.3953C>T) is classified Likely benign in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.059); Very rare (popmax 0.00738%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Pro1318Leu (c.3953C>T)?

SETD1A p.Pro1318Leu (c.3953C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Pro1318Leu (c.3953C>T) in the general population?

SETD1A p.Pro1318Leu (c.3953C>T) is very rare (popmax 0.00738%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Pro1318Leu (c.3953C>T)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

SETD1A p.Pro1318Leu

c.3953C>T · VCV3440141

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00738%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.96	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 -2.8	GERP -3.9
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.57 · regional, not allelic
Overall
CADD	8.05	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 0.00738% European (non-Finnish) · 87/1,178,428 alleles

Filtering AF 0.00606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00566%

Overall 0.00632% 101/1,598,948 alleles · very rare exomes 88/1,446,618 · genomes 13/152,330 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00738%	13,545
African / African-American	0.00667%	14,996
Admixed American	0.00502%	19,927
East Asian	0.00446%	22,401
Remaining individualsnot grpmax-eligible	0.00322%	31,084
Finnishnot grpmax-eligible	0.00194%	51,578
South Asian	0.0011%	90,826

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.Pro1318Leu
Coding: c.3953C>T
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30979739 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1318: 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

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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-pro1318leu (accessed [today's date]).

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