Is AHNAK2 p.Lys2170Arg (c.6509A>G) pathogenic?

AHNAK2 p.Lys2170Arg (c.6509A>G) is classified Benign in AHNAK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-29). AlphaMissense: likely benign (0.1005); Common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about AHNAK2 p.Lys2170Arg (c.6509A>G)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

AHNAK2 p.Lys2170Arg

Q: How common is AHNAK2 p.Lys2170Arg (c.6509A>G) in the general population?

AHNAK2 p.Lys2170Arg (c.6509A>G) is common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6509A>G · rs201127689 · VCV402352

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.127	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 0.22
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	17.14	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 17.6% Middle Eastern · 683/3,882 alleles

Filtering AF 16.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.1%

Overall 11.4% 134,363/1,177,404 alleles · common exomes 130,577/1,090,618 · genomes 3,786/86,786 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	25%	4
Middle Easterngrpmax	17.6%	6
South Asian	15.4%	7
European (non-Finnish)	12.3%	8
Remaining individualsnot grpmax-eligible	12.1%	8
Finnishnot grpmax-eligible	7.85%	13
Admixed American	5.65%	18
Amishnot grpmax-eligible	4.61%	22
African / African-American	4.32%	23
East Asian	0.354%	282

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.Lys2170Arg
Coding: c.6509A>G
MANE Select: NM_138420
dbSNP: rs201127689
Type: single nucleotide variant
Location: chr14:104948942 (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.Lys2170Glu 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-lys2170arg (accessed [today's date]).

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