Is DNHD1 p.Leu4528Phe (c.13582C>T) pathogenic?

DNHD1 p.Leu4528Phe (c.13582C>T) is classified Conflicting classifications of pathogenicity in DNHD1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.3324); Rare (popmax 0.136%, amr).

How common is DNHD1 p.Leu4528Phe (c.13582C>T) in the general population?

DNHD1 p.Leu4528Phe (c.13582C>T) is rare (popmax 0.136%, amr) (gnomAD).

What do computational predictors say about DNHD1 p.Leu4528Phe (c.13582C>T)?

AlphaMissense predicts likely benign (score 0.3324) — an in-silico prediction, not a clinical call.

DNHD1 p.Leu4528Phe

c.13582C>T · rs761155698 · VCV737498

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3324 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.3324	likely benign
REVEL	0.279	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,234 bp · p 0.2 · regional, not allelic
Overall
CADD	25.5	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 0.136% Admixed American · 81/59,472 alleles

Filtering AF 0.112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00564% 90/1,595,728 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.136%	734
East Asian	0.0134%	7,442
Remaining individualsnot grpmax-eligible	0.00324%	30,874
European (non-Finnish)	8.53e-05%	1,172,077

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.Leu4528Phe
Coding: c.13582C>T
MANE Select: NM_144666
dbSNP: rs761155698
Type: single nucleotide variant
Location: chr11:6571094 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4528: 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.Arg2928Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg3978Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg4048Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Glu1153Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Tyr2166Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg1582Trp Uncertain significance ★★ same type
DNHD1 p.Arg1873Ser Uncertain significance ★★ ⚠ same type
DNHD1 p.Arg2555Trp 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-leu4528phe (accessed [today's date]).

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