Is DYNC1H1 p.Val677Leu (c.2029G>T) pathogenic?

DYNC1H1 p.Val677Leu (c.2029G>T) is classified Uncertain significance in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-23). AlphaMissense: likely pathogenic (0.7101); Very rare (popmax 0.0011%, sas).

How common is DYNC1H1 p.Val677Leu (c.2029G>T) in the general population?

DYNC1H1 p.Val677Leu (c.2029G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DYNC1H1 p.Val677Leu (c.2029G>T)?

AlphaMissense predicts likely pathogenic (score 0.7101) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Val677Leu

c.2029G>T · rs563050462 · VCV1304517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7101	likely pathogenic
REVEL	0.168	moderately 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 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 3,602 bp · p 2.9e-46 · regional, not allelic
Overall
CADD	23.3	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 0.0011% South Asian · 1/91,056 alleles

Overall 0.000137% 2/1,461,792 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asiangrpmax	0.0011%	91,056

Remaining individuals 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: DYNC1H1
Protein: p.Val677Leu
Coding: c.2029G>T
MANE Select: NM_001376
dbSNP: rs563050462
Type: single nucleotide variant
Location: chr14:101986254 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 677: an α-helix; the 'stem' region; the 'interaction with dync1i2' region; the 'interaction with dync1li2' region

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

Similar variants

DYNC1H1 p.Val677Met Likely benign ★★ ⚠ same residue
DYNC1H1 p.Val677= Likely benign ★ same residue
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

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-val677leu (accessed [today's date]).

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