Is DOCK5 p.Met992Thr (c.2975T>C) pathogenic?

DOCK5 p.Met992Thr (c.2975T>C) is classified Uncertain significance in DOCK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.6698); Ultra-rare (popmax 0.012%, afr).

How common is DOCK5 p.Met992Thr (c.2975T>C) in the general population?

DOCK5 p.Met992Thr (c.2975T>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about DOCK5 p.Met992Thr (c.2975T>C)?

AlphaMissense predicts likely pathogenic (score 0.6698) — an in-silico prediction, not a clinical call.

DOCK5 p.Met992Thr

c.2975T>C · VCV3504492

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6698	likely pathogenic
REVEL	0.307	indeterminate
SaProt	LLR -4.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL 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 0.91	unconstrained · MANE · 107 kb · p 5.5e-05 · 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 0.012% African / African-American · 9/74,942 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000867% 14/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,327
Admixed American	0.00333%	30,005
Remaining individualsnot grpmax-eligible	0.0016%	62,466
South Asian	0.0011%	91,092
European (non-Finnish)	8.48e-05%	1,179,884

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.Met992Thr
Coding: c.2975T>C
MANE Select: NM_024940
Type: single nucleotide variant
Location: chr8:25363072 (GRCh38)
Gene constraint: LOEUF 0.679 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.63 · 11 PDB

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-met992thr (accessed [today's date]).

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