Is DYNLT4 p.Tyr168Cys (c.503A>G) pathogenic?

DYNLT4 p.Tyr168Cys (c.503A>G) is classified Uncertain significance in DYNLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.4547); Ultra-rare (popmax 0.0304%, nfe).

How common is DYNLT4 p.Tyr168Cys (c.503A>G) in the general population?

DYNLT4 p.Tyr168Cys (c.503A>G) is ultra-rare (popmax 0.0304%, nfe) (gnomAD).

What do computational predictors say about DYNLT4 p.Tyr168Cys (c.503A>G)?

AlphaMissense predicts ambiguous (score 0.4547) — an in-silico prediction, not a clinical call.

DYNLT4 p.Tyr168Cys

c.503A>G · rs373111522 · VCV2525019

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0304%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4547	ambiguous
REVEL	0.555	indeterminate
SaProt	LLR -10.10	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 662 bp · p 0.79 · regional, not allelic
Overall
CADD	24.9	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 0.0304% European (non-Finnish) · 354/1,164,510 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0268%

Overall 0.0245% 386/1,577,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.64%	61
European (non-Finnish)grpmax	0.0304%	3,290
Remaining individualsnot grpmax-eligible	0.0147%	6,803
Admixed American	0.00551%	18,135
South Asian	0.00342%	29,219
African / African-American	0.00269%	37,207

Amish 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: DYNLT4
Protein: p.Tyr168Cys
Coding: c.503A>G
MANE Select: NM_001377534
dbSNP: rs373111522
Type: single nucleotide variant
Location: chr1:44806166 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.02

Full DYNLT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DYNLT4 p.Ala130Ser Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala146Thr Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala146Val Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala195Val Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala41Ser Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala58Thr Uncertain significance ★ ⚠ same type
DYNLT4 p.Ala72Thr Uncertain significance ★ ⚠ same type
DYNLT4 p.Arg102His 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/dynlt4-p-tyr168cys (accessed [today's date]).

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