Is AHNAK2 p.Pro3151Leu (c.9452C>T) pathogenic?

AHNAK2 p.Pro3151Leu (c.9452C>T) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). AlphaMissense: likely pathogenic (0.6304); Very rare (popmax 0.00569%, afr).

How common is AHNAK2 p.Pro3151Leu (c.9452C>T) in the general population?

AHNAK2 p.Pro3151Leu (c.9452C>T) is very rare (popmax 0.00569%, afr) (gnomAD).

What do computational predictors say about AHNAK2 p.Pro3151Leu (c.9452C>T)?

AlphaMissense predicts likely pathogenic (score 0.6304) — an in-silico prediction, not a clinical call.

AHNAK2 p.Pro3151Leu

c.9452C>T · VCV3844848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6304 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00569%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6304	likely pathogenic · top 3% in AHNAK2
REVEL	0.18	moderately 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 1.4	GERP 0.3, phastCons 0.8
Regional constraint	o/e 0.52	unconstrained · MANE · 262 bp · p 3.5e-07 · regional, not allelic
Overall
CADD	19.49	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 0.00569% African / African-American · 4/70,268 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00197%

Overall 0.00313% 43/1,372,264 alleles · very rare exomes 39/1,253,292 · genomes 4/118,972 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00569%	17,567
Remaining individualsnot grpmax-eligible	0.00554%	18,065
Admixed American	0.00544%	18,392
European (non-Finnish)	0.00315%	31,737
East Asian	0.00226%	44,286
South Asian	0.00126%	79,612

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.Pro3151Leu
Coding: c.9452C>T
MANE Select: NM_138420
Type: single nucleotide variant
Location: chr14:104945999 (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.Pro3151= Likely benign ★ 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-pro3151leu (accessed [today's date]).

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