Is DNAH1 p.Arg425Leu (c.1274G>T) pathogenic?

DNAH1 p.Arg425Leu (c.1274G>T) is classified Uncertain significance in DNAH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-16). AlphaMissense: likely benign (0.2836); Ultra-rare (popmax 0.0225%, nfe); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Arg425Leu (c.1274G>T)?

DNAH1 p.Arg425Leu (c.1274G>T) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Arg425Leu (c.1274G>T) in the general population?

DNAH1 p.Arg425Leu (c.1274G>T) is ultra-rare (popmax 0.0225%, nfe) (gnomAD).

What do computational predictors say about DNAH1 p.Arg425Leu (c.1274G>T)?

AlphaMissense predicts likely benign (score 0.2836) — an in-silico prediction, not a clinical call.

DNAH1 p.Arg425Leu

c.1274G>T · rs200951874 · VCV1486238

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

spermatogenic failure 18

Computational evidence

Protein change
AlphaMissense	0.2836	likely benign
REVEL	0.169	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.67, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 30 kb · p 0.21 · regional, not allelic
Overall
CADD	13.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0225% European (non-Finnish) · 265/1,179,774 alleles

Filtering AF 0.0202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.0172% 277/1,612,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0225%	4,452
Middle Eastern	0.0164%	6,082
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Admixed American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0032%	31,229
Finnishnot grpmax-eligible	0.00316%	31,602

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.Arg425Leu
Coding: c.1274G>T
MANE Select: NM_015512
dbSNP: rs200951874
Type: single nucleotide variant
Location: chr3:52332382 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 425: the 'stem' region

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 p.Arg425His Uncertain significance ★★ ⚠ same residue
DNAH1 c.1034-2A>G Likely pathogenic ★★ same condition
DNAH1 c.10474+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAH1 c.10968+2C>T Likely pathogenic ★★ same condition
DNAH1 c.5244+1G>A Likely pathogenic ★★ same condition
DNAH1 p.Arg1702Ter Pathogenic ★★ same condition
DNAH1 p.Arg2479Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH1 p.Arg2622Ter Pathogenic/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/dnah1-p-arg425leu (accessed [today's date]).

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