Is AHNAK2 p.Pro2126fs (c.6377_6378del) pathogenic?

AHNAK2 p.Pro2126fs (c.63776378del) is classified Benign in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). Ultra-rare (popmax 0.0232%, sas).

How common is AHNAK2 p.Pro2126fs (c.6377_6378del) in the general population?

AHNAK2 p.Pro2126fs (c.6377_6378del) is ultra-rare (popmax 0.0232%, sas) (gnomAD).

AHNAK2 p.Pro2126fs

c.6377_6378del · VCV3772653

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.1	GERP -0.57
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	chr14:104943070 segmental duplication, simple repeat · ambiguous alignment · reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0232% South Asian · 15/64,574 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.0179% 190/1,064,002 alleles · ultra-rare exomes 178/958,760 · genomes 12/105,242 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.678%	147
South Asiangrpmax	0.0232%	4,305
Remaining individualsnot grpmax-eligible	0.014%	7,119
Admixed American	0.0107%	9,334
European (non-Finnish)	0.00765%	13,077
African / African-American	0.00579%	17,264

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.Pro2126fs
Coding: c.6377_6378del
MANE Select: NM_138420
Type: Deletion
Location: chr14:104949073 (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.Ala617fs Uncertain significance ★ same type
AHNAK2 p.Asp3465fs Uncertain significance ★ same type
AHNAK2 p.3472KFKMP[1] Likely benign ★ same type
AHNAK2 p.Ala1284fs Likely benign ★ same type
AHNAK2 p.Glu3560_Val3569del Benign ★ same type
AHNAK2 p.Leu2086_Asp2092del 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-pro2126fs (accessed [today's date]).

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