Is DNAH1 p.Arg3490fs (c.10468_10471del) pathogenic?

DNAH1 p.Arg3490fs (c.1046810471del) is classified Pathogenic/Likely pathogenic in DNAH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0617%, amr); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Arg3490fs (c.10468_10471del)?

DNAH1 p.Arg3490fs (c.10468_10471del) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Arg3490fs (c.10468_10471del) in the general population?

DNAH1 p.Arg3490fs (c.10468_10471del) is ultra-rare (popmax 0.0617%, amr) (gnomAD).

DNAH1 p.Arg3490fs

c.10468_10471del · rs759646845 · VCV578911

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0617%, amr)

Conditions

spermatogenic failure 18

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 65 of 78
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
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 0.0617% Admixed American · 37/60,002 alleles

Filtering AF 0.0459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.0144% 233/1,613,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0617%	1,622
Remaining individualsnot grpmax-eligible	0.0256%	3,904
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0143%	6,980
African / African-American	0.00667%	14,990
South Asian	0.00549%	18,209

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: DNAH1
Protein: p.Arg3490fs
Coding: c.10468_10471del
MANE Select: NM_015512
dbSNP: rs759646845
Type: Microsatellite
Location: chr3:52393015 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 3490: a UniProt-annotated variant site (in spgf18)

Full DNAH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ciliary dyskinesia, primary, 37

Similar variants

DNAH1 c.3694-16CCCCT[3] Benign/Likely benign ★★ same condition
DNAH1 p.Ala1047fs Pathogenic ★ same condition
DNAH1 p.Ser2663fs Pathogenic ★ same condition
DNAH1 p.Trp2468fs Pathogenic ★ same condition
DNAH1 p.Val1761fs Pathogenic ★ same condition
DNAH1 c.9622-3_9622-2del Uncertain significance ★ same condition
DNAH1 p.1579PAG[1] Uncertain significance ★ same condition
DNAH1 p.Arg3490Thr Uncertain significance ★ same residue

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/dnah1-p-arg3490fs (accessed [today's date]).

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