Is DNHD1 p.Arg3217Ter (c.9649C>T) pathogenic?

DNHD1 p.Arg3217Ter (c.9649C>T) is classified Likely pathogenic in DNHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). Ultra-rare (popmax 0.0366%, eas); Associated with spermatogenic failure 65.

What condition is associated with DNHD1 p.Arg3217Ter (c.9649C>T)?

DNHD1 p.Arg3217Ter (c.9649C>T) is associated with spermatogenic failure 65 (ClinVar).

How common is DNHD1 p.Arg3217Ter (c.9649C>T) in the general population?

DNHD1 p.Arg3217Ter (c.9649C>T) is ultra-rare (popmax 0.0366%, eas) (gnomAD).

DNHD1 p.Arg3217Ter

c.9649C>T · rs764070280 · VCV1693246

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0366%, eas)

Conditions

spermatogenic failure 65

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 29 of 43
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Constraint at this position
Conservation	phyloP 0.12	GERP -3.1, phastCons 0.87
Overall
CADD	35.0	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 0.0366% East Asian · 15/40,930 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00354% 55/1,551,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0366%	2,729
European (non-Finnish)	0.00331%	30,184
Remaining individualsnot grpmax-eligible	0.00166%	60,090
African / African-American	0.00137%	73,022

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.Arg3217Ter
Coding: c.9649C>T
MANE Select: NM_144666
dbSNP: rs764070280
Type: single nucleotide variant
Location: chr11:6563111 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 3217: 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.Arg3217Gln Likely benign ★ same residue
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

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-arg3217ter (accessed [today's date]).

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