Is DNAH5 p.Phe4281Ser (c.12842T>C) pathogenic?

DNAH5 p.Phe4281Ser (c.12842T>C) is classified Uncertain significance in DNAH5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-01). AlphaMissense: likely pathogenic (0.8751); Very rare (popmax 0.000339%, nfe); Associated with primary ciliary dyskinesia 3.

What condition is associated with DNAH5 p.Phe4281Ser (c.12842T>C)?

DNAH5 p.Phe4281Ser (c.12842T>C) is associated with primary ciliary dyskinesia 3 (ClinVar).

How common is DNAH5 p.Phe4281Ser (c.12842T>C) in the general population?

DNAH5 p.Phe4281Ser (c.12842T>C) is very rare (popmax 0.000339%, nfe) (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.Phe4281Ser (c.12842T>C)?

AlphaMissense predicts likely pathogenic (score 0.8751) — an in-silico prediction, not a clinical call.

DNAH5 p.Phe4281Ser

c.12842T>C · rs886059964 · VCV351010

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

primary ciliary dyskinesia 3

Computational evidence

Protein change
AlphaMissense	0.8751	likely pathogenic
REVEL	0.576	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.038 · regional, not allelic
Overall
CADD	23.5	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 0.000339% European (non-Finnish) · 4/1,179,894 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,848 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: DNAH5
Protein: p.Phe4281Ser
Coding: c.12842T>C
MANE Select: NM_001369
dbSNP: rs886059964
Type: single nucleotide variant
Location: chr5:13716554 (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

primary ciliary dyskinesia 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

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

Similar variants

DNAH5 c.10555+1G>C Likely pathogenic ★★ same condition
DNAH5 c.11028+2T>C Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.11571-1G>A Pathogenic ★★ same condition
DNAH5 c.12910-1G>C Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.1320+1G>A Likely pathogenic ★★ same condition
DNAH5 c.13338+1G>A Likely pathogenic ★★ same condition
DNAH5 c.1731-1G>C Pathogenic ★★ same condition
DNAH5 c.193-1G>A 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-phe4281ser (accessed [today's date]).

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