Is DNAH5 p.Arg4127Cys (c.12379C>T) pathogenic?

DNAH5 p.Arg4127Cys (c.12379C>T) is classified Conflicting classifications of pathogenicity in DNAH5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.6136); Ultra-rare (popmax 0.0217%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH5 p.Arg4127Cys (c.12379C>T)?

DNAH5 p.Arg4127Cys (c.12379C>T) is associated with primary ciliary dyskinesia, primary ciliary dyskinesia 3 (ClinVar).

How common is DNAH5 p.Arg4127Cys (c.12379C>T) in the general population?

DNAH5 p.Arg4127Cys (c.12379C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DNAH5 p.Arg4127Cys (c.12379C>T)?

AlphaMissense predicts likely pathogenic (score 0.6136) — an in-silico prediction, not a clinical call.

DNAH5 p.Arg4127Cys

c.12379C>T · rs148696723 · VCV219652

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.6136	likely pathogenic
REVEL	0.505	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 228 kb · p 0.16 · regional, not allelic
Overall
CADD	26.4	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 0.0217% Admixed American · 13/59,974 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.0083% 134/1,613,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0946%	1,057
Admixed Americangrpmax	0.0217%	4,613
European (non-Finnish)	0.00737%	13,562
Remaining individualsnot grpmax-eligible	0.0064%	15,626
East Asian	0.00223%	44,852
African / African-American	0.00134%	74,886

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg4127Cys
Coding: c.12379C>T
MANE Select: NM_001369
dbSNP: rs148696723
Type: single nucleotide variant
Location: chr5:13719002 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4127: the 'aaa 6' region

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

Disease context

primary ciliary dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary ciliary dyskinesia 3

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

DNAH5 p.Arg4127His Conflicting classifications of pathogenicity ★ ⚠ same residue
DNAH5 p.Arg4127Ser Uncertain significance ★ same residue
DNAH5 p.Arg4127= Likely benign ★ same residue
DNAH5 p.Arg4127fs 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

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-arg4127cys (accessed [today's date]).

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