Is AHNAK2 p.Asp1980Ala (c.5939A>C) pathogenic?

AHNAK2 p.Asp1980Ala (c.5939A>C) is classified Conflicting classifications of pathogenicity in AHNAK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-11). AlphaMissense: likely benign (0.2274); Rare (popmax 0.189%, afr).

How common is AHNAK2 p.Asp1980Ala (c.5939A>C) in the general population?

AHNAK2 p.Asp1980Ala (c.5939A>C) is rare (popmax 0.189%, afr) (gnomAD).

What do computational predictors say about AHNAK2 p.Asp1980Ala (c.5939A>C)?

AlphaMissense predicts likely benign (score 0.2274) — an in-silico prediction, not a clinical call.

AHNAK2 p.Asp1980Ala

c.5939A>C · rs745545200 · VCV2644769

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2274 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.189%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2274	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.23	GERP 0.58
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	13.37	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 0.189% African / African-American · 138/72,838 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.154%

Overall 0.0111% 177/1,587,560 alleles · rare exomes 80/1,441,370 · genomes 97/146,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.189%	528
Admixed American	0.0348%	2,875
Middle Eastern	0.0166%	6,036
Remaining individualsnot grpmax-eligible	0.0114%	8,795
South Asian	0.00111%	89,912
European (non-Finnish)	0.00086%	116,289

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.Asp1980Ala
Coding: c.5939A>C
MANE Select: NM_138420
dbSNP: rs745545200
Type: single nucleotide variant
Location: chr14:104949512 (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.Asp1980Glu Conflicting classifications of pathogenicity ★ ⚠ 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-asp1980ala (accessed [today's date]).

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