Is DNAH2 p.Pro4325Arg (c.12974C>G) pathogenic?

DNAH2 p.Pro4325Arg (c.12974C>G) is classified Likely benign in DNAH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2016-03-29). AlphaMissense: likely pathogenic (0.8684); Low-frequency (popmax 3.57%, nfe).

How common is DNAH2 p.Pro4325Arg (c.12974C>G) in the general population?

DNAH2 p.Pro4325Arg (c.12974C>G) is low-frequency (popmax 3.57%, nfe) (gnomAD).

What do computational predictors say about DNAH2 p.Pro4325Arg (c.12974C>G)?

AlphaMissense predicts likely pathogenic (score 0.8684) — an in-silico prediction, not a clinical call.

DNAH2 p.Pro4325Arg

c.12974C>G · rs116930996 · VCV402718

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8684 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.57%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8684	likely pathogenic
REVEL	0.314	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 4.5e-10 · regional, not allelic
Overall
CADD	25.0	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 3.57% European (non-Finnish) · 42,089/1,180,012 alleles

Filtering AF 3.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.53%

Overall 3.16% 50,994/1,614,136 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.17%	24
European (non-Finnish)grpmax	3.57%	28
South Asian	3.37%	30
Remaining individualsnot grpmax-eligible	3.11%	32
Ashkenazi Jewishnot grpmax-eligible	2.64%	38
Middle Eastern	2.47%	40
Finnishnot grpmax-eligible	2.11%	47
Admixed American	1.88%	53
African / African-American	0.585%	171
East Asian	0.0134%	7,479

Amish 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: DNAH2
Protein: p.Pro4325Arg
Coding: c.12974C>G
MANE Select: NM_020877
dbSNP: rs116930996
Type: single nucleotide variant
Location: chr17:7832924 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Residue 4325: 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

Similar variants

DNAH2 p.Ala1036Val Uncertain significance ★★ ⚠ same type
DNAH2 p.Arg1533Cys Uncertain significance ★★ ⚠ same type
DNAH2 p.Arg2538Gln Uncertain significance ★★ same type
DNAH2 p.Arg3759His Uncertain significance ★★ ⚠ same type
DNAH2 p.Gln2069Glu Uncertain significance ★★ same type
DNAH2 p.Ile4043Ser Uncertain significance ★★ ⚠ same type
DNAH2 p.Pro3819Leu Uncertain significance ★★ ⚠ same type
DNAH2 c.10169+3G>A Benign ★★ 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/dnah2-p-pro4325arg (accessed [today's date]).

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