Is DOCK3 p.Val148Met (c.442G>A) pathogenic?

DOCK3 p.Val148Met (c.442G>A) is classified Uncertain significance in DOCK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-09). AlphaMissense: likely benign (0.3071); Ultra-rare (popmax 0.0267%, eas); Associated with neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia.

How common is DOCK3 p.Val148Met (c.442G>A) in the general population?

DOCK3 p.Val148Met (c.442G>A) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about DOCK3 p.Val148Met (c.442G>A)?

AlphaMissense predicts likely benign (score 0.3071) — an in-silico prediction, not a clinical call.

DOCK3 p.Val148Met

Q: What condition is associated with DOCK3 p.Val148Met (c.442G>A)?

DOCK3 p.Val148Met (c.442G>A) is associated with neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia (ClinVar).

c.442G>A · rs772466836 · VCV2441946

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia

Computational evidence

Protein change
AlphaMissense	0.3071	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 550 kb · p 0.00035 · regional, not allelic
Overall
CADD	32.0	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,880 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00328% 53/1,613,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0048%	20,819
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.00305%	32,773
Admixed American	0.00167%	59,970

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: DOCK3
Protein: p.Val148Met
Coding: c.442G>A
MANE Select: NM_004947
dbSNP: rs772466836
Type: single nucleotide variant
Location: chr3:51064574 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.52
Residue 148: a UniProt-annotated variant site (in nedidha)

Full DOCK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK3 p.Arg392Gln Uncertain significance ★★ ⚠ same condition
DOCK3 p.Lys1296Arg Uncertain significance ★★ ⚠ same condition
DOCK3 p.Val668Met Uncertain significance ★★ ⚠ same condition
DOCK3 c.1918-3T>C Benign ★★ same condition
DOCK3 c.1038-2A>G Likely pathogenic ★ same condition
DOCK3 p.Arg2001Ter Likely pathogenic ★ same condition
DOCK3 p.Gln128Ter Pathogenic ★ same condition
DOCK3 p.Arg741Trp Uncertain significance ★ ⚠ same condition

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/dock3-p-val148met (accessed [today's date]).

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