Is SETD1A p.Pro649fs (c.1943dup) pathogenic?

SETD1A p.Pro649fs (c.1943dup) is classified Likely pathogenic in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). Very rare (popmax 0.00367%, eas); Associated with neurodevelopmental disorder with speech impairment and dysmorphic facies.

What condition is associated with SETD1A p.Pro649fs (c.1943dup)?

SETD1A p.Pro649fs (c.1943dup) is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies (ClinVar).

How common is SETD1A p.Pro649fs (c.1943dup) in the general population?

SETD1A p.Pro649fs (c.1943dup) is very rare (popmax 0.00367%, eas) (gnomAD).

SETD1A p.Pro649fs

c.1943dup · VCV4292564

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00367%, eas)

Conditions

neurodevelopmental disorder with speech impairment and dysmorphic facies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00367% East Asian · 1/27,284 alleles

Overall 8.69e-05% 1/1,151,054 alleles · very rare exomes 0/1,019,844 · genomes 1/131,210 · 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.Pro649fs
Coding: c.1943dup
MANE Select: NM_014712
Type: Duplication
Location: chr16:30965818 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 649: 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

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

Similar variants

SETD1A p.Pro543fs Likely pathogenic ★ same condition
SETD1A p.Ser1033fs Likely pathogenic ★ same condition
SETD1A p.Tyr412fs Likely pathogenic ★ same condition
SETD1A p.Gly708fs Conflicting classifications of pathogenicity ★ ⚠ same condition
SETD1A p.Thr231_Thr232insGlyThr Uncertain significance ★ same condition
SETD1A p.Ala339fs Pathogenic same condition
SETD1A c.4582-2_4582-1del Pathogenic ★★ same condition
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ 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-pro649fs (accessed [today's date]).

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