Is AHNAK2 p.Met4152Ile (c.12456G>C) pathogenic?

AHNAK2 p.Met4152Ile (c.12456G>C) is classified Likely benign in AHNAK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). AlphaMissense: likely benign (0.1009); Ultra-rare (popmax 0.0403%, afr).

How common is AHNAK2 p.Met4152Ile (c.12456G>C) in the general population?

AHNAK2 p.Met4152Ile (c.12456G>C) is ultra-rare (popmax 0.0403%, afr) (gnomAD).

What do computational predictors say about AHNAK2 p.Met4152Ile (c.12456G>C)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

AHNAK2 p.Met4152Ile

c.12456G>C · rs751865009 · VCV3100284

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0403%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign
REVEL	0.015	strongly 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 -20	GERP -1.3
Regional constraint	o/e 1.21	unconstrained · MANE · 5,079 bp · p 5.5e-23 · regional, not allelic
Overall
CADD	0.001	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 0.0403% African / African-American · 30/74,478 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.00254% 41/1,612,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0403%	2,483
Admixed American	0.00501%	19,974
Finnishnot grpmax-eligible	0.00156%	63,946
South Asian	0.0011%	91,000
European (non-Finnish)	0.000509%	196,527

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.Met4152Ile
Coding: c.12456G>C
MANE Select: NM_138420
dbSNP: rs751865009
Type: single nucleotide variant
Location: chr14:104942995 (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.Met4152Val Uncertain significance ★ ⚠ same residue
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

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-met4152ile (accessed [today's date]).

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