Is AK8 p.Pro12Arg (c.35C>G) pathogenic?

AK8 p.Pro12Arg (c.35C>G) is classified Uncertain significance in AK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.1026); Ultra-rare (popmax 0.0278%, eas).

How common is AK8 p.Pro12Arg (c.35C>G) in the general population?

AK8 p.Pro12Arg (c.35C>G) is ultra-rare (popmax 0.0278%, eas) (gnomAD).

What do computational predictors say about AK8 p.Pro12Arg (c.35C>G)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

AK8 p.Pro12Arg

c.35C>G · rs779143686 · VCV3104060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0278%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 153 kb · p 0.018 · regional, not allelic
Overall
CADD	26.1	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 0.0278% East Asian · 11/39,568 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.00336% 49/1,458,180 alleles · ultra-rare exomes 40/1,305,890 · genomes 9/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0278%	3,597
South Asian	0.0195%	5,120
African / African-American	0.00588%	16,996
Admixed American	0.00497%	20,139
Remaining individualsnot grpmax-eligible	0.00361%	27,724
European (non-Finnish)	0.00154%	64,816

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.Pro12Arg
Coding: c.35C>G
MANE Select: NM_152572
dbSNP: rs779143686
Type: single nucleotide variant
Location: chr9:132878221 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.47

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

Similar variants

AK8 p.Pro12Ala Uncertain significance ★ ⚠ same residue
AK8 p.Pro12Thr Uncertain significance ★ ⚠ same residue
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

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-pro12arg (accessed [today's date]).

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