Is AJAP1 p.Pro75Leu (c.224C>T) pathogenic?

AJAP1 p.Pro75Leu (c.224C>T) is classified Uncertain significance in AJAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.0965); Very rare (popmax 0.00535%, nfe).

How common is AJAP1 p.Pro75Leu (c.224C>T) in the general population?

AJAP1 p.Pro75Leu (c.224C>T) is very rare (popmax 0.00535%, nfe) (gnomAD).

What do computational predictors say about AJAP1 p.Pro75Leu (c.224C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

AJAP1 p.Pro75Leu

c.224C>T · VCV4030163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.5, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 119 kb · p 0.53 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% European (non-Finnish) · 62/1,158,404 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00431% 67/1,556,134 alleles · very rare exomes 61/1,404,056 · genomes 6/152,078 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00535%	18,684
Finnishnot grpmax-eligible	0.00353%	28,295
Remaining individualsnot grpmax-eligible	0.00333%	30,050
African / African-American	0.0014%	71,502

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: AJAP1
Protein: p.Pro75Leu
Coding: c.224C>T
MANE Select: NM_018836
Type: single nucleotide variant
Location: chr1:4712094 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.22

Full AJAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AJAP1 p.Pro228Arg Uncertain significance ★★ ⚠ same type
AJAP1 p.Ser260Gly Uncertain significance ★★ ⚠ same type
AJAP1 p.Ala35Val Benign ★★ same type
AJAP1 p.Gly202Asp Benign ★★ same type
AJAP1 p.Ala115Thr Uncertain significance ★ ⚠ same type
AJAP1 p.Ala122Thr Uncertain significance ★ ⚠ same type
AJAP1 p.Ala123Thr Uncertain significance ★ ⚠ same type
AJAP1 p.Ala142Val Uncertain significance ★ ⚠ 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/ajap1-p-pro75leu (accessed [today's date]).

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