Is DYNC1H1 p.Pro49Ala (c.145C>G) pathogenic?

DYNC1H1 p.Pro49Ala (c.145C>G) is classified Uncertain significance in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.000341%, nfe).

How common is DYNC1H1 p.Pro49Ala (c.145C>G) in the general population?

DYNC1H1 p.Pro49Ala (c.145C>G) is very rare (popmax 0.000341%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Pro49Ala (c.145C>G)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Pro49Ala

c.145C>G · rs1402375700 · VCV1311609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.83, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 225 bp · p 0.67 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000341% European (non-Finnish) · 4/1,174,512 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00025% 4/1,600,302 alleles · very rare exomes 3/1,448,076 · genomes 1/152,226 · 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: DYNC1H1
Protein: p.Pro49Ala
Coding: c.145C>G
MANE Select: NM_001376
dbSNP: rs1402375700
Type: single nucleotide variant
Location: chr14:101964836 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

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

Similar variants

DYNC1H1 p.Pro49Ser Uncertain significance ★ ⚠ same residue
DYNC1H1 p.Pro49= 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-pro49ala (accessed [today's date]).

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