Is SETD1A p.Val24Met (c.70G>A) pathogenic?

SETD1A p.Val24Met (c.70G>A) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-22). AlphaMissense: ambiguous (0.341); Very rare (popmax 0.000339%, nfe); Associated with neurodevelopmental disorder with speech impairment and dysmorphic facies.

How common is SETD1A p.Val24Met (c.70G>A) in the general population?

SETD1A p.Val24Met (c.70G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Val24Met (c.70G>A)?

AlphaMissense predicts ambiguous (score 0.341) — an in-silico prediction, not a clinical call.

SETD1A p.Val24Met

Q: What condition is associated with SETD1A p.Val24Met (c.70G>A)?

SETD1A p.Val24Met (c.70G>A) is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies, epilepsy, early-onset, with or without developmental delay (ClinVar).

c.70G>A · VCV3580264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

neurodevelopmental disorder with speech impairment and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.341	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -7.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 432 bp · p 0.038 · regional, not allelic
Overall
CADD	27.9	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 0.000339% European (non-Finnish) · 4/1,179,996 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,172 alleles · very rare exomes 5/1,461,848 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)grpmax	0.000339%	294,999

Finnish 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.Val24Met
Coding: c.70G>A
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30958801 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB

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

Disease context

neurodevelopmental disorder with speech impairment and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epilepsy, early-onset, with or without developmental delay

Similar variants

SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg668Ter Pathogenic ★★ same condition
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same condition
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg1392His Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg1418His Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp 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-val24met (accessed [today's date]).

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