Is SETD1A p.Phe249Leu (c.745T>C) pathogenic?

SETD1A p.Phe249Leu (c.745T>C) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-21). AlphaMissense: likely pathogenic (0.8957); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Phe249Leu (c.745T>C)?

SETD1A p.Phe249Leu (c.745T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Phe249Leu (c.745T>C) in the general population?

SETD1A p.Phe249Leu (c.745T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SETD1A p.Phe249Leu (c.745T>C)?

AlphaMissense predicts likely pathogenic (score 0.8957) — an in-silico prediction, not a clinical call.

SETD1A p.Phe249Leu

c.745T>C · VCV3794599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8957	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,694 bp · p 0.44 · regional, not allelic
Overall
CADD	24.9	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 0.00267% African / African-American · 2/74,882 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,960 alleles · very rare exomes 6/1,461,880 · genomes 2/152,080 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-Americangrpmax	0.00267%	37,441
European (non-Finnish)	8.47e-05%	1,180,006

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe249Leu
Coding: c.745T>C
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30964199 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 249: 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.Phe249= Likely benign ★ 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-phe249leu (accessed [today's date]).

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