Is AHNAK p.Pro463Ser (c.1387C>T) pathogenic?

AHNAK p.Pro463Ser (c.1387C>T) is classified Conflicting classifications of pathogenicity in AHNAK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-27). AlphaMissense: likely benign (0.1249); Rare (popmax 0.223%, afr).

How common is AHNAK p.Pro463Ser (c.1387C>T) in the general population?

AHNAK p.Pro463Ser (c.1387C>T) is rare (popmax 0.223%, afr) (gnomAD).

What do computational predictors say about AHNAK p.Pro463Ser (c.1387C>T)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

AHNAK p.Pro463Ser

c.1387C>T · rs200763732 · VCV726306

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.068	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 5.5	GERP -1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.28 · regional, not allelic
Overall
CADD	16.68	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 0.223% African / African-American · 167/74,986 alleles

Filtering AF 0.195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.0116% 188/1,613,866 alleles · rare exomes 80/1,461,696 · genomes 108/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.223%	449
Admixed American	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.0096%	10,417
East Asian	0.00223%	44,886
European (non-Finnish)	8.47e-05%	1,179,942

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: AHNAK
Protein: p.Pro463Ser
Coding: c.1387C>T
MANE Select: NM_001620
dbSNP: rs200763732
Type: single nucleotide variant
Location: chr11:62533030 (GRCh38)
Gene constraint: LOEUF 0.793 · pLI <0.01 (gnomAD)

Full AHNAK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AHNAK p.Asn3289His Uncertain significance ★★ ⚠ same type
AHNAK p.Gly365Val Uncertain significance ★★ ⚠ same type
AHNAK p.Ala3588= Benign/Likely benign ★★ same type
AHNAK p.Arg1063Lys Benign ★★ same type
AHNAK p.Arg1272Pro Benign ★★ same type
AHNAK p.Asn3587Ser Benign ★★ same type
AHNAK p.Asp1493= Benign ★★ same type
AHNAK p.Asp2459= 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/ahnak-p-pro463ser (accessed [today's date]).

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