Is DNAH2 p.Arg3100Trp (c.9298C>T) pathogenic?

DNAH2 p.Arg3100Trp (c.9298C>T) is classified Pathogenic in DNAH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-11-12). AlphaMissense: likely benign (0.3287); Very rare (popmax 0.008%, afr); Associated with spermatogenic failure 45.

What condition is associated with DNAH2 p.Arg3100Trp (c.9298C>T)?

DNAH2 p.Arg3100Trp (c.9298C>T) is associated with spermatogenic failure 45 (ClinVar).

How common is DNAH2 p.Arg3100Trp (c.9298C>T) in the general population?

DNAH2 p.Arg3100Trp (c.9298C>T) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about DNAH2 p.Arg3100Trp (c.9298C>T)?

AlphaMissense predicts likely benign (score 0.3287) — an in-silico prediction, not a clinical call.

DNAH2 p.Arg3100Trp

c.9298C>T · rs201414958 · VCV984732

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Conditions

spermatogenic failure 45

Computational evidence

Protein change
AlphaMissense	0.3287	likely benign ⚠ discordant with ClinVar
REVEL	0.459	indeterminate
Splicing
SpliceAI	Δ0.97	donor gain · deltas
Pangolin	Δ0.87	gain · loss 0.79 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.8	GERP -3.4, phastCons 0.002
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 4.5e-10 · regional, not allelic
Overall
CADD	35.0	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 0.008% African / African-American · 6/74,990 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00155% 25/1,613,194 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,498
East Asian	0.00669%	14,955
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
Admixed American	0.00167%	59,950
European (non-Finnish)	0.00119%	84,239

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.Arg3100Trp
Coding: c.9298C>T
MANE Select: NM_020877
dbSNP: rs201414958
Type: single nucleotide variant
Location: chr17:7805072 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Residue 3100: the 'stalk' region; a UniProt-annotated variant site (in spgf45; uncertain significance; decreased protein abundance)

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

Disease context

spermatogenic failure 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAH2 p.Arg1533Cys Uncertain significance ★★ ⚠ same condition
DNAH2 c.12460-2A>G Likely pathogenic ★ same condition
DNAH2 c.7145+1G>A Likely pathogenic ★ same condition
DNAH2 p.Arg1924Cys Likely pathogenic ★ same condition
DNAH2 p.Arg3882Ter Pathogenic ★ same condition
DNAH2 p.Gln1076Ter Likely pathogenic ★ same condition
DNAH2 p.Lys1273Ter Likely pathogenic ★ same condition
DNAH2 p.Trp2902Ter 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/dnah2-p-arg3100trp (accessed [today's date]).

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