Is AHNAK2 p.Arg83Ile (c.248G>T) pathogenic?

AHNAK2 p.Arg83Ile (c.248G>T) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.5196); Rare (popmax 0.119%, sas).

How common is AHNAK2 p.Arg83Ile (c.248G>T) in the general population?

AHNAK2 p.Arg83Ile (c.248G>T) is rare (popmax 0.119%, sas) (gnomAD).

What do computational predictors say about AHNAK2 p.Arg83Ile (c.248G>T)?

AlphaMissense predicts ambiguous (score 0.5196) — an in-silico prediction, not a clinical call.

AHNAK2 p.Arg83Ile

c.248G>T · rs777735794 · VCV3100824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5196 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, sas)

Computational evidence

Protein change
AlphaMissense	0.5196	ambiguous · top 5% in AHNAK2
REVEL	0.112	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	24.1	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 0.119% South Asian · 108/91,086 alleles

Filtering AF 0.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0936%

Overall 0.00706% 114/1,613,896 alleles · rare exomes 110/1,461,548 · genomes 4/152,348 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.119%	843
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	8.48e-05%	1,179,871

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.Arg83Ile
Coding: c.248G>T
MANE Select: NM_138420
dbSNP: rs777735794
Type: single nucleotide variant
Location: chr14:104956655 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Residue 83: the 'disordered' region

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-arg83ile (accessed [today's date]).

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