Is DNAH8 p.Ile4488Val (c.13462A>G) pathogenic?

DNAH8 p.Ile4488Val (c.13462A>G) is classified Benign in DNAH8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0672); Common (popmax 21.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Ile4488Val (c.13462A>G)?

DNAH8 p.Ile4488Val (c.13462A>G) is associated with primary ciliary dyskinesia (ClinVar).

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.Ile4488Val (c.13462A>G)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

DNAH8 p.Ile4488Val

Q: How common is DNAH8 p.Ile4488Val (c.13462A>G) in the general population?

DNAH8 p.Ile4488Val (c.13462A>G) is common (popmax 21.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.13462A>G · rs10484847 · VCV257630

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.037	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.9, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 112 kb · p 0.0022 · regional, not allelic
Overall
CADD	8.866	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 I4271V vs ClinVar I4488V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.2% Middle Eastern · 1,281/6,048 alleles

Filtering AF 20.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.8%

Overall 15.5% 250,241/1,611,998 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	26.7%	4
Middle Easterngrpmax	21.2%	5
European (non-Finnish)	16.5%	6
Remaining individualsnot grpmax-eligible	16%	6
African / African-American	13.8%	7
South Asian	13.5%	7
Admixed American	12.2%	8
Amishnot grpmax-eligible	11.6%	9
Finnishnot grpmax-eligible	10.8%	9
East Asian	0.225%	444

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: DNAH8
Protein: p.Ile4488Val
Coding: c.13462A>G
MANE Select: NM_001206927
dbSNP: rs10484847
Type: single nucleotide variant
Location: chr6:39012305 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 4488: 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 p.Ile4488Leu Uncertain significance ★ ⚠ same residue
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

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-ile4488val (accessed [today's date]).

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