Is CD226 p.Glu19Lys (c.55G>A) pathogenic?

CD226 p.Glu19Lys (c.55G>A) is classified Uncertain significance in CD226 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.101); Rare (popmax 0.157%, afr).

How common is CD226 p.Glu19Lys (c.55G>A) in the general population?

CD226 p.Glu19Lys (c.55G>A) is rare (popmax 0.157%, afr) (gnomAD).

What do computational predictors say about CD226 p.Glu19Lys (c.55G>A)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

CD226 p.Glu19Lys

c.55G>A · VCV4222719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	phastCons 0.19
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.44 · regional, not allelic
Overall
CADD	14.6	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 0.157% African / African-American · 118/74,986 alleles

Filtering AF 0.134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.008% 129/1,612,456 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.157%	635
Remaining individualsnot grpmax-eligible	0.0112%	8,918
Admixed American	0.005%	20,000
South Asian	0.0011%	90,984

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: CD226
Protein: p.Glu19Lys
Coding: c.55G>A
MANE Select: NM_001303618
Type: single nucleotide variant
Location: chr18:69947061 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.75 · 2 PDB
Residue 19: the ig-like c2-type 1 domain

Full CD226 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD226 p.Ala133Val Uncertain significance ★ ⚠ same type
CD226 p.Ala16Gly Uncertain significance ★ ⚠ same type
CD226 p.Ala226Thr Uncertain significance ★ ⚠ same type
CD226 p.Ala76Thr Uncertain significance ★ ⚠ same type
CD226 p.Ala76Val Uncertain significance ★ ⚠ same type
CD226 p.Ala9Pro Uncertain significance ★ ⚠ same type
CD226 p.Arg193Gly Uncertain significance ★ ⚠ same type
CD226 p.Asn198Thr 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/cd226-p-glu19lys (accessed [today's date]).

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