Is DYNC1H1 p.Phe277Val (c.829T>G) pathogenic?

DYNC1H1 p.Phe277Val (c.829T>G) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-06-12). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with Distal lower limb muscle weakness.

What condition is associated with DYNC1H1 p.Phe277Val (c.829T>G)?

DYNC1H1 p.Phe277Val (c.829T>G) is associated with Distal lower limb muscle weakness (ClinVar).

How common is DYNC1H1 p.Phe277Val (c.829T>G) in the general population?

DYNC1H1 p.Phe277Val (c.829T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Phe277Val (c.829T>G)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Phe277Val

c.829T>G · rs1057518935 · VCV374156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Distal lower limb muscle weakness

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 6% in DYNC1H1
REVEL	0.858	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 16 kb · p 5.6e-17 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYNC1H1
Protein: p.Phe277Val
Coding: c.829T>G
MANE Select: NM_001376
dbSNP: rs1057518935
Type: single nucleotide variant
Location: chr14:101980418 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 277: the 'stem' region; an α-helix

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Distal lower limb muscle weakness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC1H1 c.4396-1G>C Likely pathogenic ★★ same type
DYNC1H1 p.Ala4519Val Likely pathogenic ★★ same type
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same type
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same type
DYNC1H1 p.Arg1623Trp Pathogenic ★★ same type
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same type
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same type
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ 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/dync1h1-p-phe277val (accessed [today's date]).

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