Is AHNAK2 p.Asp2085Ala (c.6254A>C) pathogenic?

AHNAK2 p.Asp2085Ala (c.6254A>C) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely benign (0.2529); Very rare (popmax 0.00638%, amr).

How common is AHNAK2 p.Asp2085Ala (c.6254A>C) in the general population?

AHNAK2 p.Asp2085Ala (c.6254A>C) is very rare (popmax 0.00638%, amr) (gnomAD).

What do computational predictors say about AHNAK2 p.Asp2085Ala (c.6254A>C)?

AlphaMissense predicts likely benign (score 0.2529) — an in-silico prediction, not a clinical call.

AHNAK2 p.Asp2085Ala

c.6254A>C · VCV4027211

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00638%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2529	likely benign
REVEL	0.086	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.53, phastCons 0.11
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	16.84	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00638% Admixed American · 3/47,020 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.0014% 15/1,072,092 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00641%	15,592
Admixed Americangrpmax	0.00638%	15,673
African / African-American	0.00562%	17,789
European (non-Finnish)	0.000951%	105,104

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp2085Ala
Coding: c.6254A>C
MANE Select: NM_138420
Type: single nucleotide variant
Location: chr14:104949197 (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.Asp2085Gly Uncertain significance ★ ⚠ 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-asp2085ala (accessed [today's date]).

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