Is SETD1A p.Pro435fs (c.1304del) pathogenic?

SETD1A p.Pro435fs (c.1304del) is classified Pathogenic in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). Very rare (popmax 6.2e-05%).

How common is SETD1A p.Pro435fs (c.1304del) in the general population?

SETD1A p.Pro435fs (c.1304del) is very rare (popmax 6.2e-05%) (gnomAD).

SETD1A p.Pro435fs

c.1304del · rs2143492454 · VCV1275794

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

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 7 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.5	GERP -5.4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,611,726 alleles · very rare exomes 1/1,459,944 · genomes 0/151,782 · 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.Pro435fs
Coding: c.1304del
MANE Select: NM_014712
dbSNP: rs2143492454
Type: Deletion
Location: chr16:30965042 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 435: a UniProt-annotated variant site (in nedsid); the 'disordered' region

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

Similar variants

SETD1A p.Pro435Arg Uncertain significance ★ ⚠ same residue
SETD1A p.Pro435Leu Likely benign ★ same residue
SETD1A c.4582-2_4582-1del Pathogenic ★★ same type
SETD1A p.Pro644fs Pathogenic ★★ same type
SETD1A c.2682+8_2682+9del Likely benign ★★ same type
SETD1A p.Ala1323fs Likely pathogenic ★ same type
SETD1A p.Ala777fs Likely pathogenic ★ same type
SETD1A p.Arg72fs 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-pro435fs (accessed [today's date]).

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