Is CNKSR2 p.Glu926Val (c.2777A>T) pathogenic?

CNKSR2 p.Glu926Val (c.2777A>T) is classified Uncertain significance in CNKSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.3006); Very rare (popmax 0.00621%, nfe).

How common is CNKSR2 p.Glu926Val (c.2777A>T) in the general population?

CNKSR2 p.Glu926Val (c.2777A>T) is very rare (popmax 0.00621%, nfe) (gnomAD).

What do computational predictors say about CNKSR2 p.Glu926Val (c.2777A>T)?

AlphaMissense predicts likely benign (score 0.3006) — an in-silico prediction, not a clinical call.

CNKSR2 p.Glu926Val

c.2777A>T · VCV3342874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00621%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3006	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -7.75	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 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 57 kb · p 1.8e-06 · regional, not allelic
Overall
CADD	23.8	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 0.00621% European (non-Finnish) · 55/886,112 alleles

Filtering AF 0.00488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00438%

Overall 0.00468% 56/1,195,354 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00621%	16,111
Remaining individualsnot grpmax-eligible	0.00212%	47,216

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: CNKSR2
Protein: p.Glu926Val
Coding: c.2777A>T
MANE Select: NM_014927
Type: single nucleotide variant
Location: chrX:21648915 (GRCh38)
Structure: AlphaFold pLDDT 57.67 · 2 PDB
Residue 926: a UniProt-annotated variant site (in mrxshg)

Full CNKSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNKSR2 p.Arg400Ter Pathogenic/Likely pathogenic ★★ same type
CNKSR2 p.Arg438Ter Likely pathogenic ★★ same type
CNKSR2 p.Arg712Ter Pathogenic ★★ same type
CNKSR2 p.Arg729Ter Pathogenic/Likely pathogenic ★★ same type
CNKSR2 c.741+4A>G Uncertain significance ★★ same type
CNKSR2 p.Cys718Ser Uncertain significance ★★ ⚠ same type
CNKSR2 p.Glu407Lys Uncertain significance ★★ ⚠ same type
CNKSR2 p.Glu882Lys 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/cnksr2-p-glu926val (accessed [today's date]).

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