Is DNHD1 p.Pro4469fs (c.13388_13404dup) pathogenic?

DNHD1 p.Pro4469fs (c.1338813404dup) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-28). Very rare (popmax 0.00133%, afr).

How common is DNHD1 p.Pro4469fs (c.13388_13404dup) in the general population?

DNHD1 p.Pro4469fs (c.13388_13404dup) is very rare (popmax 0.00133%, afr) (gnomAD).

DNHD1 p.Pro4469fs

c.13388_13404dup · VCV3342712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 42 of 43
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.7	GERP -3.2
Overall
CADD	21.7	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 0.00133% African / African-American · 1/74,954 alleles

Overall 0.000657% 1/152,254 alleles · very rare

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: DNHD1
Protein: p.Pro4469fs
Coding: c.13388_13404dup
MANE Select: NM_144666
Type: Duplication
Location: chr11:6570895 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4469: a UniProt-annotated variant site (in spgf65); a UniProt-annotated variant site (in spgf65; low expression, if any, in sperm flagella)

Full DNHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNHD1 p.Pro4469Ser Uncertain significance ★ ⚠ same residue
DNHD1 p.Leu1268fs Likely pathogenic ★ same type
DNHD1 p.Leu4499fs Pathogenic ★ same type
DNHD1 p.Ala4572_Ser4573insAspAla Uncertain significance ★ same type
DNHD1 p.Ala545fs Uncertain significance ★ same type
DNHD1 p.Gln4623fs Uncertain significance ★ same type
DNHD1 p.Thr3268fs Uncertain significance ★ 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/dnhd1-p-pro4469fs (accessed [today's date]).

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