Is AK9 p.Val997Phe (c.2989G>T) pathogenic?

AK9 p.Val997Phe (c.2989G>T) is classified Uncertain significance in AK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1555); Ultra-rare (popmax 0.0876%, amr).

How common is AK9 p.Val997Phe (c.2989G>T) in the general population?

AK9 p.Val997Phe (c.2989G>T) is ultra-rare (popmax 0.0876%, amr) (gnomAD).

What do computational predictors say about AK9 p.Val997Phe (c.2989G>T)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

AK9 p.Val997Phe

c.2989G>T · VCV3280057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0876%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -2.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Pangolin	Δ0.35	gain · loss 0.33 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP -0.16	GERP -4.1
Regional constraint	o/e 0.93	unconstrained · MANE · 147 kb · p 0.0059 · regional, not allelic
Overall
CADD	2.497	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 0.0876% Admixed American · 42/47,938 alleles

Filtering AF 0.0666% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0592%

Overall 0.00926% 121/1,306,734 alleles · ultra-rare exomes 117/1,167,572 · genomes 4/139,162 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0876%	1,141
East Asian	0.0202%	4,961
South Asian	0.0187%	5,345
Ashkenazi Jewishnot grpmax-eligible	0.0155%	6,433
Finnishnot grpmax-eligible	0.00764%	13,085
Remaining individualsnot grpmax-eligible	0.00686%	14,575
European (non-Finnish)	0.00505%	19,784
African / African-American	0.00158%	63,158

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: AK9
Protein: p.Val997Phe
Coding: c.2989G>T
MANE Select: NM_001145128
Type: single nucleotide variant
Location: chr6:109546103 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.70
Residue 997: the 'adenylate kinase 2' region

Full AK9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AK9 c.1254+12A>T Uncertain significance ★★ same type
AK9 c.1254+19G>A Uncertain significance ★★ same type
FIG4 c.-365A>G Likely benign ★★ same type
AK9 c.3225+1G>A Likely pathogenic ★ same type
AK9 p.Ala124Thr Uncertain significance ★ ⚠ same type
AK9 p.Ala1428Asp Uncertain significance ★ ⚠ same type
AK9 p.Ala1619Thr Uncertain significance ★ ⚠ same type
AK9 p.Ala1723Thr 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/ak9-p-val997phe (accessed [today's date]).

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