Is AHNAK2 p.Phe151Leu (c.451T>C) pathogenic?

AHNAK2 p.Phe151Leu (c.451T>C) is classified Uncertain significance in AHNAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely pathogenic (0.974); Very rare (popmax 0.00754%, nfe).

How common is AHNAK2 p.Phe151Leu (c.451T>C) in the general population?

AHNAK2 p.Phe151Leu (c.451T>C) is very rare (popmax 0.00754%, nfe) (gnomAD).

What do computational predictors say about AHNAK2 p.Phe151Leu (c.451T>C)?

AlphaMissense predicts likely pathogenic (score 0.974) — an in-silico prediction, not a clinical call.

AHNAK2 p.Phe151Leu

c.451T>C · rs201598898 · VCV3101086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.974	likely pathogenic · top 1% in AHNAK2
REVEL	0.141	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; 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 6.7	GERP -0.77, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 32 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	22.1	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 0.00754% European (non-Finnish) · 89/1,179,620 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00558% 90/1,613,160 alleles · very rare exomes 82/1,460,846 · genomes 8/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00754%	13,254
African / African-American	0.00133%	75,040

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.Phe151Leu
Coding: c.451T>C
MANE Select: NM_138420
dbSNP: rs201598898
Type: single nucleotide variant
Location: chr14:104955498 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Residue 151: the pdz domain

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-phe151leu (accessed [today's date]).

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