Is DOCK5 p.Tyr45His (c.133T>C) pathogenic?

DOCK5 p.Tyr45His (c.133T>C) is classified Uncertain significance in DOCK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely pathogenic (0.7846); Ultra-rare (popmax 0.0109%, afr).

How common is DOCK5 p.Tyr45His (c.133T>C) in the general population?

DOCK5 p.Tyr45His (c.133T>C) is ultra-rare (popmax 0.0109%, afr) (gnomAD).

What do computational predictors say about DOCK5 p.Tyr45His (c.133T>C)?

AlphaMissense predicts likely pathogenic (score 0.7846) — an in-silico prediction, not a clinical call.

DOCK5 p.Tyr45His

c.133T>C · rs986730924 · VCV3085028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7846	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -13.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 116 kb · p 0.58 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% African / African-American · 8/73,276 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.000636% 10/1,571,360 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0109%	9,160
Remaining individualsnot grpmax-eligible	0.00164%	60,858
European (non-Finnish)	8.61e-05%	1,161,904

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: DOCK5
Protein: p.Tyr45His
Coding: c.133T>C
MANE Select: NM_024940
dbSNP: rs986730924
Type: single nucleotide variant
Location: chr8:25268850 (GRCh38)
Gene constraint: LOEUF 0.679 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.63 · 11 PDB
Residue 45: the sh3 domain

Full DOCK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK5 c.4788+9C>T Benign ★★ same type
DOCK5 p.Leu986Phe Benign/Likely benign ★★ same type
DOCK5 p.Met987Leu Benign ★★ same type
DOCK5 p.Pro1467= Benign ★★ same type
DOCK5 p.Ser1306= Benign ★★ same type
DOCK5 p.Thr469Met Benign/Likely benign ★★ ⚠ same type
DOCK5 p.Ala1067Val Uncertain significance ★ ⚠ same type
DOCK5 p.Ala1194Ser 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/dock5-p-tyr45his (accessed [today's date]).

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