Is AHNAK2 p.Val1289Met (c.3865G>A) pathogenic?

AHNAK2 p.Val1289Met (c.3865G>A) is classified Conflicting classifications of pathogenicity in AHNAK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-01). AlphaMissense: likely benign (0.1073); Ultra-rare (popmax 0.0589%, nfe).

How common is AHNAK2 p.Val1289Met (c.3865G>A) in the general population?

AHNAK2 p.Val1289Met (c.3865G>A) is ultra-rare (popmax 0.0589%, nfe) (gnomAD).

What do computational predictors say about AHNAK2 p.Val1289Met (c.3865G>A)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

AHNAK2 p.Val1289Met

c.3865G>A · rs200117223 · VCV2587985

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0589%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -0.45
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	2.059	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0589% European (non-Finnish) · 519/881,066 alleles

Filtering AF 0.0547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.053%

Overall 0.0582% 726/1,247,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.794%	126
European (non-Finnish)grpmax	0.0589%	1,698
Remaining individualsnot grpmax-eligible	0.0508%	1,967
Finnishnot grpmax-eligible	0.0371%	2,697
Middle Eastern	0.025%	4,002
Admixed American	0.0093%	10,754
African / African-American	0.00141%	70,928

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AHNAK2
Protein: p.Val1289Met
Coding: c.3865G>A
MANE Select: NM_138420
dbSNP: rs200117223
Type: single nucleotide variant
Location: chr14:104951586 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)

Full AHNAK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AHNAK2 p.Glu3598Lys Uncertain significance ★★ ⚠ same type
AHNAK2 p.Gly4376Ser Uncertain significance ★★ ⚠ same type
AHNAK2 p.Lys2479Arg Uncertain significance ★★ ⚠ same type
AHNAK2 p.Lys3309Asn Uncertain significance ★★ ⚠ same type
AHNAK2 p.Val1351Met Uncertain significance ★★ ⚠ same type
AHNAK2 p.Ala1115Val Benign/Likely benign ★★ same type
AHNAK2 p.Ala1323Thr Likely benign ★★ same type
AHNAK2 p.Ala1818Thr Benign/Likely benign ★★ 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/ahnak2-p-val1289met (accessed [today's date]).

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