Is AHNAK2 p.Pro1200Ser (c.3598C>T) pathogenic?

AHNAK2 p.Pro1200Ser (c.3598C>T) is classified Conflicting classifications of pathogenicity in AHNAK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1378); Rare (popmax 0.25%, afr).

How common is AHNAK2 p.Pro1200Ser (c.3598C>T) in the general population?

AHNAK2 p.Pro1200Ser (c.3598C>T) is rare (popmax 0.25%, afr) (gnomAD).

What do computational predictors say about AHNAK2 p.Pro1200Ser (c.3598C>T)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

AHNAK2 p.Pro1200Ser

c.3598C>T · rs200524362 · VCV2644844

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.25%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.71	GERP -1.6, phastCons 0.021
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	16.56	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 0.25% African / African-American · 183/73,326 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.0517% 829/1,602,446 alleles · rare exomes 641/1,460,078 · genomes 188/142,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.25%	401
Middle Eastern	0.202%	496
South Asian	0.127%	790
East Asian	0.0872%	1,147
Remaining individualsnot grpmax-eligible	0.0772%	1,296
European (non-Finnish)	0.0349%	2,864
Admixed American	0.0323%	3,099
Ashkenazi Jewishnot grpmax-eligible	0.00685%	14,592
Finnishnot grpmax-eligible	0.00317%	31,545

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.Pro1200Ser
Coding: c.3598C>T
MANE Select: NM_138420
dbSNP: rs200524362
Type: single nucleotide variant
Location: chr14:104951853 (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.Pro1200Leu Uncertain significance ★ ⚠ same residue
AHNAK2 p.Pro1200= 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

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-pro1200ser (accessed [today's date]).

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