Is AHNAK p.Pro4189Ser (c.12565C>T) pathogenic?

AHNAK p.Pro4189Ser (c.12565C>T) is classified Uncertain significance in AHNAK (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-10). AlphaMissense: likely pathogenic (0.8825); Ultra-rare (popmax 0.0202%, afr).

How common is AHNAK p.Pro4189Ser (c.12565C>T) in the general population?

AHNAK p.Pro4189Ser (c.12565C>T) is ultra-rare (popmax 0.0202%, afr) (gnomAD).

What do computational predictors say about AHNAK p.Pro4189Ser (c.12565C>T)?

AlphaMissense predicts likely pathogenic (score 0.8825) — an in-silico prediction, not a clinical call.

AHNAK p.Pro4189Ser

c.12565C>T · VCV4868348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.8825	likely pathogenic · top 1% in AHNAK
REVEL	0.275	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.28 · regional, not allelic
Overall
CADD	19.56	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 0.0202% African / African-American · 15/74,300 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00143% 23/1,612,494 alleles · ultra-rare exomes 13/1,461,894 · genomes 10/150,600 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0202%	4,953
Middle Eastern	0.0165%	6,076
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.000339%	294,938

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.Pro4189Ser
Coding: c.12565C>T
MANE Select: NM_001620
Type: single nucleotide variant
Location: chr11:62521852 (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-pro4189ser (accessed [today's date]).

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