Is AHNAK2 p.Pro3476Ser (c.10426C>T) pathogenic?

AHNAK2 p.Pro3476Ser (c.10426C>T) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely pathogenic (0.7657); Ultra-rare (popmax 0.0148%, nfe).

How common is AHNAK2 p.Pro3476Ser (c.10426C>T) in the general population?

AHNAK2 p.Pro3476Ser (c.10426C>T) is ultra-rare (popmax 0.0148%, nfe) (gnomAD).

What do computational predictors say about AHNAK2 p.Pro3476Ser (c.10426C>T)?

AlphaMissense predicts likely pathogenic (score 0.7657) — an in-silico prediction, not a clinical call.

AHNAK2 p.Pro3476Ser

c.10426C>T · rs376878100 · VCV3100050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7657 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.7657	likely pathogenic · top 2% in AHNAK2
REVEL	0.171	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 4.4	GERP -0.61, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 5,079 bp · p 5.5e-23 · regional, not allelic
Overall
CADD	20.7	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 0.0148% European (non-Finnish) · 175/1,179,256 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0116% 187/1,612,356 alleles · ultra-rare exomes 169/1,461,242 · genomes 18/151,114 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0148%	6,739
Remaining individualsnot grpmax-eligible	0.00801%	12,484
African / African-American	0.00671%	14,914
Admixed American	0.00334%	29,954

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.Pro3476Ser
Coding: c.10426C>T
MANE Select: NM_138420
dbSNP: rs376878100
Type: single nucleotide variant
Location: chr14:104945025 (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-pro3476ser (accessed [today's date]).

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