Is DNAH8 p.Arg1369Ser (c.4107A>T) pathogenic?

DNAH8 p.Arg1369Ser (c.4107A>T) is classified Uncertain significance in DNAH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.6119); Ultra-rare (popmax 0.035%, sas).

How common is DNAH8 p.Arg1369Ser (c.4107A>T) in the general population?

DNAH8 p.Arg1369Ser (c.4107A>T) is ultra-rare (popmax 0.035%, sas) (gnomAD).

What do computational predictors say about DNAH8 p.Arg1369Ser (c.4107A>T)?

AlphaMissense predicts likely pathogenic (score 0.6119) — an in-silico prediction, not a clinical call.

DNAH8 p.Arg1369Ser

c.4107A>T · VCV4661110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6119	likely pathogenic
REVEL	0.135	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP -0.78, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 131 kb · p 0.0001 · regional, not allelic
Overall
CADD	17.18	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 R1152S vs ClinVar R1369S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% South Asian · 30/85,646 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00213% 34/1,595,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.035%	2,855
Remaining individualsnot grpmax-eligible	0.00161%	61,926
European (non-Finnish)	0.000256%	390,781

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.Arg1369Ser
Coding: c.4107A>T
MANE Select: NM_001206927
Type: single nucleotide variant
Location: chr6:38828207 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 1369: 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

Similar variants

DNAH8 c.10963-1G>A Likely pathogenic ★★ same type
DNAH8 c.11563+1G>T Likely pathogenic ★★ same type
DNAH8 c.2664+2T>C Likely pathogenic ★★ same type
DNAH8 c.5734-1G>T Likely pathogenic ★★ same type
DNAH8 p.Arg1090Ter Pathogenic/Likely pathogenic ★★ same type
DNAH8 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same type
DNAH8 p.Arg2878Ter Pathogenic ★★ same type
DNAH8 p.Arg4166Ter Pathogenic/Likely pathogenic ★★ same type

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-arg1369ser (accessed [today's date]).

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