Is DOCK9 p.Ser757Ala (c.2269T>G) pathogenic?

DOCK9 p.Ser757Ala (c.2269T>G) is classified Conflicting classifications of pathogenicity in DOCK9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.0566); Rare (popmax 0.495%, mid).

How common is DOCK9 p.Ser757Ala (c.2269T>G) in the general population?

DOCK9 p.Ser757Ala (c.2269T>G) is rare (popmax 0.495%, mid) (gnomAD).

What do computational predictors say about DOCK9 p.Ser757Ala (c.2269T>G)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

DOCK9 p.Ser757Ala

c.2269T>G · rs200500566 · VCV736290

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.48	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 5.1	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 140 kb · p 1.2e-07 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S758A vs ClinVar S757A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.495% Middle Eastern · 30/6,056 alleles

Filtering AF 0.357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.309%

Overall 0.0832% 1,342/1,613,684 alleles · rare exomes 1,216/1,461,382 · genomes 126/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.495%	202
Admixed American	0.182%	550
Remaining individualsnot grpmax-eligible	0.107%	932
European (non-Finnish)	0.0927%	1,078
Ashkenazi Jewishnot grpmax-eligible	0.0778%	1,286
South Asian	0.0121%	8,271
African / African-American	0.00933%	10,717
East Asian	0.00223%	44,884

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: DOCK9
Protein: p.Ser757Ala
Coding: c.2269T>G
MANE Select: NM_001366683
dbSNP: rs200500566
Type: single nucleotide variant
Location: chr13:98885084 (GRCh38)
Gene constraint: LOEUF 0.425 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68 · 4 PDB
Residue 758 UniProt numbering: the c2 dock-type domain

Full DOCK9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK9 p.Ala434Val Benign ★★ same type
DOCK9 p.Asn1709= Benign ★★ same type
DOCK9 p.Cys2012= Benign/Likely benign ★★ same type
DOCK9 p.Leu1435= Benign ★★ same type
DOCK9 c.5023+908C>T Uncertain significance ★ ⚠ same type
DOCK9 c.5023+919C>T Uncertain significance ★ ⚠ same type
DOCK9 c.5023+952C>T Uncertain significance ★ ⚠ same type
DOCK9 c.5367+706T>A 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/dock9-p-ser757ala (accessed [today's date]).

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