Is DNAH1 p.Phe2144Leu (c.6430T>C) pathogenic?

DNAH1 p.Phe2144Leu (c.6430T>C) is classified Uncertain significance in DNAH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). AlphaMissense: likely pathogenic (0.8476); Very rare (popmax 0.00859%, amr); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Phe2144Leu (c.6430T>C)?

DNAH1 p.Phe2144Leu (c.6430T>C) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Phe2144Leu (c.6430T>C) in the general population?

DNAH1 p.Phe2144Leu (c.6430T>C) is very rare (popmax 0.00859%, amr) (gnomAD).

What do computational predictors say about DNAH1 p.Phe2144Leu (c.6430T>C)?

AlphaMissense predicts likely pathogenic (score 0.8476) — an in-silico prediction, not a clinical call.

DNAH1 p.Phe2144Leu

c.6430T>C · rs768096962 · VCV1417543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00859%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

spermatogenic failure 18

Computational evidence

Protein change
AlphaMissense	0.8476	likely pathogenic
REVEL	0.175	moderately 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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 42 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	23.3	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 0.00859% Admixed American · 5/58,198 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00212%

Overall 0.000345% 5/1,451,188 alleles · very rare

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.Phe2144Leu
Coding: c.6430T>C
MANE Select: NM_015512
dbSNP: rs768096962
Type: single nucleotide variant
Location: chr3:52370730 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 2144: 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.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
DNAH1 p.Arg2724Ter 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-phe2144leu (accessed [today's date]).

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