Is DNAH8 p.Ser4320Pro (c.12958T>C) pathogenic?

DNAH8 p.Ser4320Pro (c.12958T>C) is classified Uncertain significance in DNAH8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.8716); Very rare (popmax 0.00405%, afr); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Ser4320Pro (c.12958T>C)?

DNAH8 p.Ser4320Pro (c.12958T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Ser4320Pro (c.12958T>C) in the general population?

DNAH8 p.Ser4320Pro (c.12958T>C) is very rare (popmax 0.00405%, afr) (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 DNAH8 p.Ser4320Pro (c.12958T>C)?

AlphaMissense predicts likely pathogenic (score 0.8716) — an in-silico prediction, not a clinical call.

DNAH8 p.Ser4320Pro

c.12958T>C · rs765743748 · VCV407273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, afr)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.8716	likely pathogenic
REVEL	0.419	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 112 kb · p 0.0022 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S4103P vs ClinVar S4320P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00405% African / African-American · 3/74,046 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000557%

Overall 0.00108% 17/1,569,508 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00405%	24,682
European (non-Finnish)	0.00123%	81,496

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: DNAH8
Protein: p.Ser4320Pro
Coding: c.12958T>C
MANE Select: NM_001206927
dbSNP: rs765743748
Type: single nucleotide variant
Location: chr6:38984212 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 4320: a UniProt-annotated variant site (found in a patient with primary ciliary dyskinesia; uncertain significance)

Full DNAH8 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

For Primary ciliary dyskinesia (Orphanet):

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

Similar variants

DNAH8 c.10963-1G>A Likely pathogenic ★★ same condition
DNAH8 c.11563+1G>T Likely pathogenic ★★ same condition
DNAH8 c.2664+2T>C Likely pathogenic ★★ same condition
DNAH8 c.5734-1G>T Likely pathogenic ★★ same condition
DNAH8 p.Arg1090Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg2878Ter Pathogenic ★★ same condition
DNAH8 p.Arg4166Ter 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/dnah8-p-ser4320pro (accessed [today's date]).

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