Is AHNAK2 p.Ala2174Val (c.6521C>T) pathogenic?

AHNAK2 p.Ala2174Val (c.6521C>T) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-21). AlphaMissense: likely benign (0.1375); Ultra-rare (popmax 0.022%, afr).

How common is AHNAK2 p.Ala2174Val (c.6521C>T) in the general population?

AHNAK2 p.Ala2174Val (c.6521C>T) is ultra-rare (popmax 0.022%, afr) (gnomAD).

What do computational predictors say about AHNAK2 p.Ala2174Val (c.6521C>T)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

AHNAK2 p.Ala2174Val

c.6521C>T · VCV3510970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.056	moderately 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 -4.5	GERP -0.52
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	17.85	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.022% African / African-American · 16/72,634 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00219% 34/1,555,792 alleles · ultra-rare exomes 23/1,428,832 · genomes 11/126,960 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.022%	4,540
Admixed American	0.0104%	9,600
East Asian	0.00899%	11,120
Remaining individualsnot grpmax-eligible	0.00658%	15,208
South Asian	0.00112%	89,140
European (non-Finnish)	0.000264%	378,811

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.Ala2174Val
Coding: c.6521C>T
MANE Select: NM_138420
Type: single nucleotide variant
Location: chr14:104948930 (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-ala2174val (accessed [today's date]).

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