Is AHNAK2 p.Ala3500Val (c.10499C>T) pathogenic?

AHNAK2 p.Ala3500Val (c.10499C>T) is classified Likely benign in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.0351%, sas).

How common is AHNAK2 p.Ala3500Val (c.10499C>T) in the general population?

AHNAK2 p.Ala3500Val (c.10499C>T) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

What do computational predictors say about AHNAK2 p.Ala3500Val (c.10499C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

AHNAK2 p.Ala3500Val

c.10499C>T · rs374100559 · VCV2365892

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0748	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 -14	GERP -0.94
Regional constraint	o/e 1.21	unconstrained · MANE · 5,079 bp · p 5.5e-23 · regional, not allelic
Overall
CADD	0.033	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 0.0351% South Asian · 32/91,058 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00422% 68/1,613,064 alleles · ultra-rare exomes 65/1,461,396 · genomes 3/151,668 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Middle Eastern	0.0329%	3,037
Remaining individualsnot grpmax-eligible	0.00961%	10,406
Admixed American	0.005%	19,990
East Asian	0.00447%	22,380
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.0017%	58,982
Finnishnot grpmax-eligible	0.00157%	63,874
African / African-American	0.00134%	74,732

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.Ala3500Val
Coding: c.10499C>T
MANE Select: NM_138420
dbSNP: rs374100559
Type: single nucleotide variant
Location: chr14:104944952 (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.Ala3500Glu Uncertain significance ★ ⚠ same residue
AHNAK2 p.Ala3500= 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

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-ala3500val (accessed [today's date]).

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