Is AK2 p.Ser208Ala (c.622T>G) pathogenic?

AK2 p.Ser208Ala (c.622T>G) is classified Uncertain significance in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.0852); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with AK2 p.Ser208Ala (c.622T>G)?

AK2 p.Ser208Ala (c.622T>G) is associated with Inborn genetic diseases (ClinVar).

How common is AK2 p.Ser208Ala (c.622T>G) in the general population?

AK2 p.Ser208Ala (c.622T>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AK2 p.Ser208Ala (c.622T>G)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

AK2 p.Ser208Ala

c.622T>G · rs776378314 · VCV2252607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.06	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 3.4	GERP -0.69, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	16.57	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 0.005% Admixed American · 3/59,982 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000743% 12/1,614,000 alleles · very rare exomes 9/1,461,886 · genomes 3/152,114 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,994
European (non-Finnish)	0.000763%	131,114

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: AK2
Protein: p.Ser208Ala
Coding: c.622T>G
MANE Select: NM_001625
dbSNP: rs776378314
Type: single nucleotide variant
Location: chr1:33013279 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 208: a β-strand

Full AK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AK2 p.Ser208= Likely benign ★★ same residue
AK2 p.Ser208Pro Uncertain significance ★ ⚠ same residue
AK2 p.Ala212Thr Uncertain significance ★★ ⚠ same condition
AK2 p.Ala2Val Uncertain significance ★★ ⚠ same condition
AK2 p.Ala32Thr Uncertain significance ★★ ⚠ same condition
AK2 p.Gly169Arg Uncertain significance ★★ ⚠ same condition
AK2 p.His43Arg Uncertain significance ★★ ⚠ same condition
AK2 p.Leu224Val 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/ak2-p-ser208ala (accessed [today's date]).

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