Is DNAH6 p.Val754Ala (c.2261T>C) pathogenic?

DNAH6 p.Val754Ala (c.2261T>C) is classified Uncertain significance in DNAH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.5824); Very rare (popmax 0.0011%, sas).

How common is DNAH6 p.Val754Ala (c.2261T>C) in the general population?

DNAH6 p.Val754Ala (c.2261T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DNAH6 p.Val754Ala (c.2261T>C)?

AlphaMissense predicts likely pathogenic (score 0.5824) — an in-silico prediction, not a clinical call.

DNAH6 p.Val754Ala

c.2261T>C · VCV4242677

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.5824	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 186 kb · p 2.6e-08 · regional, not allelic
Overall
CADD	19.84	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Overall 6.2e-05% 1/1,614,144 alleles · very rare exomes 1/1,461,836 · genomes 0/152,308 · joint denominator

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: DNAH6
Protein: p.Val754Ala
Coding: c.2261T>C
MANE Select: NM_001370
Type: single nucleotide variant
Location: chr2:84584030 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 (gnomAD)
Residue 754: the 'stem' region

Full DNAH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAH6 p.Arg3087His Uncertain significance ★★ same type
DNAH6 p.Arg3153Cys Uncertain significance ★★ ⚠ same type
DNAH6 p.Arg3292Cys Uncertain significance ★★ same type
DNAH6 p.Asp1222Asn Uncertain significance ★★ same type
DNAH6 p.Glu2899Lys Uncertain significance ★★ same type
DNAH6 p.Glu3799Lys Uncertain significance ★★ ⚠ same type
DNAH6 p.Leu3494Ile Uncertain significance ★★ ⚠ same type
DNAH6 p.Met1506Val Uncertain significance ★★ 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/dnah6-p-val754ala (accessed [today's date]).

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