Is DNHD1 p.Val4745Ala (c.14234T>C) pathogenic?

DNHD1 p.Val4745Ala (c.14234T>C) is classified Uncertain significance in DNHD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely pathogenic (0.5854); Ultra-rare (popmax 0.0826%, nfe); Associated with spermatogenic failure 65.

What condition is associated with DNHD1 p.Val4745Ala (c.14234T>C)?

DNHD1 p.Val4745Ala (c.14234T>C) is associated with spermatogenic failure 65 (ClinVar).

How common is DNHD1 p.Val4745Ala (c.14234T>C) in the general population?

DNHD1 p.Val4745Ala (c.14234T>C) is ultra-rare (popmax 0.0826%, nfe) (gnomAD).

What do computational predictors say about DNHD1 p.Val4745Ala (c.14234T>C)?

AlphaMissense predicts likely pathogenic (score 0.5854) — an in-silico prediction, not a clinical call.

DNHD1 p.Val4745Ala

c.14234T>C · rs185616789 · VCV1693250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

spermatogenic failure 65

Computational evidence

Protein change
AlphaMissense	0.5854	likely pathogenic · top 10% in DNHD1
REVEL	0.212	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,234 bp · p 0.2 · regional, not allelic
Overall
CADD	23.4	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 0.0826% European (non-Finnish) · 973/1,178,348 alleles

Filtering AF 0.0782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0765%

Overall 0.0924% 1,489/1,611,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.71%	141
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)grpmax	0.0826%	1,211
Remaining individualsnot grpmax-eligible	0.0802%	1,247
African / African-American	0.012%	8,328
Admixed American	0.00334%	29,971

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val4745Ala
Coding: c.14234T>C
MANE Select: NM_144666
dbSNP: rs185616789
Type: single nucleotide variant
Location: chr11:6571958 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4745: a UniProt-annotated variant site (in spgf65); a UniProt-annotated variant site (in spgf65; low expression, if any, in sperm flagella); a UniProt-annotated variant site (in spgf65; uncertain significance)

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-val4745ala (accessed [today's date]).

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