Is AHNAK2 p.Arg2862Ser (c.8584C>A) pathogenic?

AHNAK2 p.Arg2862Ser (c.8584C>A) is classified Benign in AHNAK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-06-05). AlphaMissense: likely benign (0.0777); Common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about AHNAK2 p.Arg2862Ser (c.8584C>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

AHNAK2 p.Arg2862Ser

Q: How common is AHNAK2 p.Arg2862Ser (c.8584C>A) in the general population?

AHNAK2 p.Arg2862Ser (c.8584C>A) is common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8584C>A · rs2582514 · VCV1269124

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 69.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.025	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 -1.6	GERP -0.61
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	0.058	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 69.9% African / African-American · 51,711/73,926 alleles

Filtering AF 69.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.2%

Overall 54.5% 877,696/1,611,362 alleles · common exomes 791,106/1,461,016 · genomes 86,590/150,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	69.9%	1
Middle Eastern	68%	1
Ashkenazi Jewishnot grpmax-eligible	65.5%	2
South Asian	61.8%	2
Remaining individualsnot grpmax-eligible	56.5%	2
European (non-Finnish)	54%	2
Admixed American	51%	2
Amishnot grpmax-eligible	46.5%	2
Finnishnot grpmax-eligible	40.6%	2
East Asian	39.6%	3

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.Arg2862Ser
Coding: c.8584C>A
MANE Select: NM_138420
dbSNP: rs2582514
Type: single nucleotide variant
Location: chr14:104946867 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Residue 2862: a UniProt-annotated variant site (in)

Full AHNAK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AHNAK2 p.Arg2862Pro 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-arg2862ser (accessed [today's date]).

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