Is DNHD1 p.Leu750Pro (c.2249T>C) pathogenic?

DNHD1 p.Leu750Pro (c.2249T>C) is classified Likely pathogenic in DNHD1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.8799); Absent from gnomAD v4.1; Associated with spermatogenic failure 65.

What condition is associated with DNHD1 p.Leu750Pro (c.2249T>C)?

DNHD1 p.Leu750Pro (c.2249T>C) is associated with spermatogenic failure 65 (ClinVar).

How common is DNHD1 p.Leu750Pro (c.2249T>C) in the general population?

DNHD1 p.Leu750Pro (c.2249T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNHD1 p.Leu750Pro (c.2249T>C)?

AlphaMissense predicts likely pathogenic (score 0.8799) — an in-silico prediction, not a clinical call.

DNHD1 p.Leu750Pro

c.2249T>C · VCV4853822

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8799 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,551,406)

Conditions

spermatogenic failure 65

Computational evidence

Protein change
AlphaMissense	0.8799	likely pathogenic ✓ concordant with ClinVar · top 2% in DNHD1
REVEL	0.298	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	22.7	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

No allele count reported in gnomAD v4.1 (AN 1,551,406). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DNHD1
Protein: p.Leu750Pro
Coding: c.2249T>C
MANE Select: NM_144666
Type: single nucleotide variant
Location: chr11:6529023 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)

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

Disease context

spermatogenic failure 65 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNHD1 p.Arg2928Ter Pathogenic/Likely pathogenic ★★ same condition
DNHD1 p.Arg3978Ter Pathogenic/Likely pathogenic ★★ same condition
DNHD1 p.Arg4048Ter Pathogenic/Likely pathogenic ★★ same condition
DNHD1 p.Glu1153Ter Pathogenic/Likely pathogenic ★★ same condition
DNHD1 p.Tyr2166Ter Pathogenic/Likely pathogenic ★★ same condition
DNHD1 p.Arg3342Gln Uncertain significance ★★ same condition
DNHD1 p.Ala1354Thr Benign/Likely benign ★★ same condition
DNHD1 p.Glu947Ter Likely benign ★★ 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/dnhd1-p-leu750pro (accessed [today's date]).

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