Is SETD5 p.Pro1415fs (c.4243_4244del) pathogenic?

SETD5 p.Pro1415fs (c.42434244del) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-14). Ultra-rare (popmax 0.064%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD5 p.Pro1415fs (c.4243_4244del)?

SETD5 p.Pro1415fs (c.4243_4244del) is associated with Inborn genetic diseases, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (ClinVar).

How common is SETD5 p.Pro1415fs (c.4243_4244del) in the general population?

SETD5 p.Pro1415fs (c.4243_4244del) is ultra-rare (popmax 0.064%, afr) (gnomAD).

SETD5 p.Pro1415fs

c.4243_4244del · rs775402365 · VCV1385729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.064%, afr)

Conditions

Inborn genetic diseases

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	escapes	premature termination codon in the last exon (23 of 23) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, 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 0.064% African / African-American · 48/75,008 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.00322% 52/1,613,916 alleles · ultra-rare exomes 26/1,461,710 · genomes 26/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.064%	1,563
Admixed American	0.005%	20,005
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: SETD5
Protein: p.Pro1415fs
Coding: c.4243_4244del
MANE Select: NM_001080517
dbSNP: rs775402365
Type: Deletion
Location: chr3:9476004 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 1415: a UniProt-annotated variant site (in mrd23); the 'disordered' region

Full SETD5 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

Also linked: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Similar variants

SETD5 p.Gln224fs Pathogenic ★★ same condition
SETD5 p.Ser1286fs Pathogenic/Likely pathogenic ★★ same condition
SETD5 p.Ala641fs Likely pathogenic ★ same condition
SETD5 p.Arg290fs Pathogenic ★ same condition
SETD5 p.Arg513fs Pathogenic ★ same condition
SETD5 p.Arg589fs Pathogenic ★ same condition
SETD5 p.Asn345fs Pathogenic ★ same condition
SETD5 p.Asn573fs 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/setd5-p-pro1415fs (accessed [today's date]).

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