Is AHNAK2 p.Pro4301Ser (c.12901C>T) pathogenic?

AHNAK2 p.Pro4301Ser (c.12901C>T) is classified Conflicting classifications of pathogenicity in AHNAK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-15). AlphaMissense: likely pathogenic (0.6591); Ultra-rare (popmax 0.026%, nfe).

How common is AHNAK2 p.Pro4301Ser (c.12901C>T) in the general population?

AHNAK2 p.Pro4301Ser (c.12901C>T) is ultra-rare (popmax 0.026%, nfe) (gnomAD).

What do computational predictors say about AHNAK2 p.Pro4301Ser (c.12901C>T)?

AlphaMissense predicts likely pathogenic (score 0.6591) — an in-silico prediction, not a clinical call.

AHNAK2 p.Pro4301Ser

c.12901C>T · rs201567366 · VCV2591029

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6591	likely pathogenic · top 3% in AHNAK2
REVEL	0.127	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 4.7	GERP -0.36, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 5,079 bp · p 5.5e-23 · regional, not allelic
Overall
CADD	19.57	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 0.026% European (non-Finnish) · 307/1,179,584 alleles

Filtering AF 0.0236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0227%

Overall 0.0206% 332/1,613,004 alleles · ultra-rare exomes 323/1,461,486 · genomes 9/151,518 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.026%	3,842
Remaining individualsnot grpmax-eligible	0.024%	4,162
Admixed American	0.00667%	14,985
Finnishnot grpmax-eligible	0.00626%	15,985
African / African-American	0.00268%	37,353

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.Pro4301Ser
Coding: c.12901C>T
MANE Select: NM_138420
dbSNP: rs201567366
Type: single nucleotide variant
Location: chr14:104942550 (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-pro4301ser (accessed [today's date]).

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