Is AHNAK2 p.Leu1020Ser (c.3059T>C) pathogenic?

AHNAK2 p.Leu1020Ser (c.3059T>C) is classified Likely benign in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.0407); Ultra-rare (popmax 0.0837%, sas).

How common is AHNAK2 p.Leu1020Ser (c.3059T>C) in the general population?

AHNAK2 p.Leu1020Ser (c.3059T>C) is ultra-rare (popmax 0.0837%, sas) (gnomAD).

What do computational predictors say about AHNAK2 p.Leu1020Ser (c.3059T>C)?

AlphaMissense predicts likely benign (score 0.0407) — an in-silico prediction, not a clinical call.

AHNAK2 p.Leu1020Ser

c.3059T>C · rs573718762 · VCV2226003

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0407 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0837%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0407	likely benign
REVEL	0.075	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 -0.066	GERP -1.7, phastCons 0.002
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	0.777	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 0.0837% South Asian · 76/90,830 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.063%

Overall 0.0193% 310/1,608,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0837%	1,195
Middle Eastern	0.0832%	1,202
Admixed American	0.0269%	3,718
African / African-American	0.0245%	4,081
Remaining individualsnot grpmax-eligible	0.0193%	5,186
European (non-Finnish)	0.0143%	6,969
East Asian	0.0135%	7,421
Finnishnot grpmax-eligible	0.011%	9,050
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,438

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.Leu1020Ser
Coding: c.3059T>C
MANE Select: NM_138420
dbSNP: rs573718762
Type: single nucleotide variant
Location: chr14:104952392 (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.Leu1020Met Likely benign ★ 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-leu1020ser (accessed [today's date]).

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