Is AHNAK2 p.Ala3957= (c.11871C>T) pathogenic?

AHNAK2 p.Ala3957= (c.11871C>T) is classified Likely benign in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). Ultra-rare (popmax 0.0221%, nfe).

How common is AHNAK2 p.Ala3957= (c.11871C>T) in the general population?

AHNAK2 p.Ala3957= (c.11871C>T) is ultra-rare (popmax 0.0221%, nfe) (gnomAD).

AHNAK2 p.Ala3957=

c.11871C>T · rs375246824 · VCV2644649

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -1.1
Overall
CADD	0.458	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0221% European (non-Finnish) · 261/1,179,520 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0335% 541/1,612,848 alleles · ultra-rare exomes 463/1,461,516 · genomes 78/151,332 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.408%	245
European (non-Finnish)grpmax	0.0221%	4,519
Remaining individualsnot grpmax-eligible	0.016%	6,245
African / African-American	0.00536%	18,674
Admixed American	0.00334%	29,952
East Asian	0.00223%	44,762
South Asian	0.0022%	45,500

Finnish 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.Ala3957=
Coding: c.11871C>T
MANE Select: NM_138420
dbSNP: rs375246824
Type: single nucleotide variant
Location: chr14:104943580 (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.Ala3957Val 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-ala3957 (accessed [today's date]).

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