Is DNAH1 p.Ser649Ile (c.1946G>T) pathogenic?

DNAH1 p.Ser649Ile (c.1946G>T) is classified Uncertain significance in DNAH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely pathogenic (0.6871); Very rare (popmax 8.53e-05%, nfe); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Ser649Ile (c.1946G>T)?

DNAH1 p.Ser649Ile (c.1946G>T) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Ser649Ile (c.1946G>T) in the general population?

DNAH1 p.Ser649Ile (c.1946G>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about DNAH1 p.Ser649Ile (c.1946G>T)?

AlphaMissense predicts likely pathogenic (score 0.6871) — an in-silico prediction, not a clinical call.

DNAH1 p.Ser649Ile

c.1946G>T · rs1379716951 · VCV2937808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

spermatogenic failure 18

Computational evidence

Protein change
AlphaMissense	0.6871	likely pathogenic
REVEL	0.193	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 30 kb · p 0.21 · regional, not allelic
Overall
CADD	24.8	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 8.53e-05% European (non-Finnish) · 1/1,172,098 alleles

Overall 6.89e-05% 1/1,452,214 alleles · very rare

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: DNAH1
Protein: p.Ser649Ile
Coding: c.1946G>T
MANE Select: NM_015512
dbSNP: rs1379716951
Type: single nucleotide variant
Location: chr3:52346761 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 649: the 'stem' region

Full DNAH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ciliary dyskinesia, primary, 37

Similar variants

DNAH1 p.Ser649Asn Uncertain significance ★ ⚠ same residue
DNAH1 c.1034-2A>G Likely pathogenic ★★ same condition
DNAH1 c.10474+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAH1 c.10968+2C>T Likely pathogenic ★★ same condition
DNAH1 c.5244+1G>A Likely pathogenic ★★ same condition
DNAH1 p.Arg1702Ter Pathogenic ★★ same condition
DNAH1 p.Arg2479Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH1 p.Arg2622Ter Pathogenic/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/dnah1-p-ser649ile (accessed [today's date]).

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