Is AHNAK2 p.Leu142Pro (c.425T>C) pathogenic?

AHNAK2 p.Leu142Pro (c.425T>C) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-29). AlphaMissense: likely pathogenic (0.9208); Ultra-rare (popmax 0.0217%, amr).

How common is AHNAK2 p.Leu142Pro (c.425T>C) in the general population?

AHNAK2 p.Leu142Pro (c.425T>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about AHNAK2 p.Leu142Pro (c.425T>C)?

AlphaMissense predicts likely pathogenic (score 0.9208) — an in-silico prediction, not a clinical call.

AHNAK2 p.Leu142Pro

c.425T>C · rs754124779 · VCV3101070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9208	likely pathogenic · top 1% in AHNAK2
REVEL	0.203	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -1, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	25.4	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 0.0217% Admixed American · 13/60,010 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00242% 39/1,613,660 alleles · ultra-rare exomes 32/1,461,318 · genomes 7/152,342 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.00186%	53,627
African / African-American	0.00133%	75,054

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.Leu142Pro
Coding: c.425T>C
MANE Select: NM_138420
dbSNP: rs754124779
Type: single nucleotide variant
Location: chr14:104955524 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Residue 142: the pdz domain

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-leu142pro (accessed [today's date]).

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