Is DNAH5 p.Arg3539Cys (c.10615C>T) pathogenic?

DNAH5 p.Arg3539Cys (c.10615C>T) is classified Pathogenic/Likely pathogenic in DNAH5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.8051); Ultra-rare (popmax 0.0164%, mid); Associated with DNAH5-related disorders.

What condition is associated with DNAH5 p.Arg3539Cys (c.10615C>T)?

DNAH5 p.Arg3539Cys (c.10615C>T) is associated with DNAH5-related disorders, primary ciliary dyskinesia 3, primary ciliary dyskinesia (ClinVar).

How common is DNAH5 p.Arg3539Cys (c.10615C>T) in the general population?

DNAH5 p.Arg3539Cys (c.10615C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DNAH5 p.Arg3539Cys (c.10615C>T)?

AlphaMissense predicts likely pathogenic (score 0.8051) — an in-silico prediction, not a clinical call.

DNAH5 p.Arg3539Cys

c.10615C>T · rs1304504006 · VCV525386

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

DNAH5-related disorders

Computational evidence

Protein change
AlphaMissense	0.8051	likely pathogenic ✓ concordant with ClinVar
REVEL	0.884	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 228 kb · p 0.16 · regional, not allelic
Overall
CADD	25.3	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00149% 24/1,613,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.004%	24,969
European (non-Finnish)	0.00161%	62,103
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: DNAH5
Protein: p.Arg3539Cys
Coding: c.10615C>T
MANE Select: NM_001369
dbSNP: rs1304504006
Type: single nucleotide variant
Location: chr5:13753490 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full DNAH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DNAH5-related disorders

Also linked: primary ciliary dyskinesia 3 primary ciliary dyskinesia

Similar variants

DNAH5 p.Arg3539His Pathogenic/Likely pathogenic ★★ same residue
DNAH5 p.Arg3539Pro Likely pathogenic ★ same residue
DNAH5 c.10555+1G>C Likely pathogenic ★★ same condition
DNAH5 c.1089+1G>A Pathogenic ★★ same condition
DNAH5 c.11028+2T>C Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.11029-2A>T Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.11571-1G>A Pathogenic ★★ same condition
DNAH5 c.12910-1G>C 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/dnah5-p-arg3539cys (accessed [today's date]).

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