Is AK8 p.Ile172Ser (c.515T>G) pathogenic?

AK8 p.Ile172Ser (c.515T>G) is classified Uncertain significance in AK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely pathogenic (0.6969); Very rare (popmax 6.35e-05%).

How common is AK8 p.Ile172Ser (c.515T>G) in the general population?

AK8 p.Ile172Ser (c.515T>G) is very rare (popmax 6.35e-05%) (gnomAD).

What do computational predictors say about AK8 p.Ile172Ser (c.515T>G)?

AlphaMissense predicts likely pathogenic (score 0.6969) — an in-silico prediction, not a clinical call.

AK8 p.Ile172Ser

c.515T>G · rs768761114 · VCV2496295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.35e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6969	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 153 kb · p 0.018 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.35e-05%

Overall 6.35e-05% 1/1,573,640 alleles · very rare exomes 1/1,421,360 · genomes 0/152,280 · joint denominator

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: AK8
Protein: p.Ile172Ser
Coding: c.515T>G
MANE Select: NM_152572
dbSNP: rs768761114
Type: single nucleotide variant
Location: chr9:132828054 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.47
Residue 172: the 'adenylate kinase 1' region

Full AK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AK8 p.Ala116Gly Uncertain significance ★ ⚠ same type
AK8 p.Ala116Val Uncertain significance ★ ⚠ same type
AK8 p.Ala265Thr Uncertain significance ★ ⚠ same type
AK8 p.Ala67Thr Uncertain significance ★ ⚠ same type
AK8 p.Ala74Gly Uncertain significance ★ ⚠ same type
AK8 p.Arg125Cys Uncertain significance ★ ⚠ same type
AK8 p.Arg125His Uncertain significance ★ ⚠ same type
AK8 p.Arg179Ser 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/ak8-p-ile172ser (accessed [today's date]).

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