Is DNAH2 p.Val4357Asp (c.13070T>A) pathogenic?

DNAH2 p.Val4357Asp (c.13070T>A) is classified Benign in DNAH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-18). AlphaMissense: likely pathogenic (0.6292); Common (popmax 20.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with DNAH2-related disorder.

What condition is associated with DNAH2 p.Val4357Asp (c.13070T>A)?

DNAH2 p.Val4357Asp (c.13070T>A) is associated with DNAH2-related disorder (ClinVar).

What do computational predictors say about DNAH2 p.Val4357Asp (c.13070T>A)?

AlphaMissense predicts likely pathogenic (score 0.6292) — an in-silico prediction, not a clinical call.

DNAH2 p.Val4357Asp

Q: How common is DNAH2 p.Val4357Asp (c.13070T>A) in the general population?

DNAH2 p.Val4357Asp (c.13070T>A) is common (popmax 20.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.13070T>A · rs78354379 · VCV3059076

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6292 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 20.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

DNAH2-related disorder

Computational evidence

Protein change
AlphaMissense	0.6292	likely pathogenic
REVEL	0.414	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 4.5e-10 · regional, not allelic
Overall
CADD	26.2	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 20.7% East Asian · 9,273/44,848 alleles

Filtering AF 20.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.2%

Overall 1.64% 26,461/1,610,344 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	20.7%	5
Admixed American	3.42%	29
South Asian	2.45%	41
Remaining individualsnot grpmax-eligible	2.18%	46
Middle Eastern	2.02%	50
Ashkenazi Jewishnot grpmax-eligible	1.83%	55
European (non-Finnish)	0.882%	113
African / African-American	0.376%	266
Finnishnot grpmax-eligible	0.306%	326

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: DNAH2
Protein: p.Val4357Asp
Coding: c.13070T>A
MANE Select: NM_020877
dbSNP: rs78354379
Type: single nucleotide variant
Location: chr17:7833162 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Residue 4357: a UniProt-annotated variant site (in spgf45; decreased protein abundance; loss of inner dynein arm assembly; in spermatozoa from patients)

Full DNAH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DNAH2-related disorder

Similar variants

DNAH2 p.Arg1633Gly Uncertain significance ⚠ same condition
DNAH2 c.11478+4G>A Benign same condition
DNAH2 c.1171-715G>A Likely benign same condition
DNAH2 c.1377-9C>A Likely benign same condition
DNAH2 c.1904+123T>C Benign same condition
DNAH2 c.1904+136C>T Likely benign same condition
DNAH2 c.1904+345A>G Likely benign same condition
DNAH2 c.3179+4C>T Likely benign 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/dnah2-p-val4357asp (accessed [today's date]).

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