Is AHNAK2 p.Pro2041Ala (c.6121C>G) pathogenic?

AHNAK2 p.Pro2041Ala (c.6121C>G) is classified Conflicting classifications of pathogenicity in AHNAK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0827); Rare (popmax 0.39%, eas).

How common is AHNAK2 p.Pro2041Ala (c.6121C>G) in the general population?

AHNAK2 p.Pro2041Ala (c.6121C>G) is rare (popmax 0.39%, eas) (gnomAD).

What do computational predictors say about AHNAK2 p.Pro2041Ala (c.6121C>G)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

AHNAK2 p.Pro2041Ala

c.6121C>G · rs570119913 · VCV2644755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.39%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.128	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 -1.3	GERP 0.57
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	16.66	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 0.39% East Asian · 173/44,364 alleles

Filtering AF 0.342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.324%

Overall 0.0154% 227/1,471,242 alleles · rare exomes 207/1,355,218 · genomes 20/116,024 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.39%	256
African / African-American	0.0381%	2,627
Remaining individualsnot grpmax-eligible	0.0121%	8,236
Admixed American	0.0113%	8,845
South Asian	0.00357%	28,007
European (non-Finnish)	0.00102%	97,589

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.Pro2041Ala
Coding: c.6121C>G
MANE Select: NM_138420
dbSNP: rs570119913
Type: single nucleotide variant
Location: chr14:104949330 (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-pro2041ala (accessed [today's date]).

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