Is DNHD1 p.Arg4048Ter (c.12142C>T) pathogenic?

DNHD1 p.Arg4048Ter (c.12142C>T) is classified Pathogenic/Likely pathogenic in DNHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-22). Ultra-rare (popmax 0.0913%, nfe); Associated with spermatogenic failure 65.

What condition is associated with DNHD1 p.Arg4048Ter (c.12142C>T)?

DNHD1 p.Arg4048Ter (c.12142C>T) is associated with spermatogenic failure 65 (ClinVar).

How common is DNHD1 p.Arg4048Ter (c.12142C>T) in the general population?

DNHD1 p.Arg4048Ter (c.12142C>T) is ultra-rare (popmax 0.0913%, nfe) (gnomAD).

DNHD1 p.Arg4048Ter

c.12142C>T · rs201118703 · VCV2053035

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0913%, nfe)

Conditions

spermatogenic failure 65

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 36 of 43
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP 0.68, phastCons 0.14
Overall
CADD	38.0	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 0.0913% European (non-Finnish) · 1,077/1,179,904 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0849%

Overall 0.0715% 1,154/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0913%	1,096
Remaining individualsnot grpmax-eligible	0.0432%	2,314
Admixed American	0.0383%	2,610
African / African-American	0.0187%	5,362
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.0141%	7,102
East Asian	0.00223%	44,878
South Asian	0.0022%	45,543

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.Arg4048Ter
Coding: c.12142C>T
MANE Select: NM_144666
dbSNP: rs201118703
Type: single nucleotide variant
Location: chr11:6567651 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 4048: 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

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.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
DNHD1 c.3325+2T>C 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/dnhd1-p-arg4048ter (accessed [today's date]).

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