Is EAPP p.Pro173Leu (c.518C>T) pathogenic?

EAPP p.Pro173Leu (c.518C>T) is classified Uncertain significance in EAPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.4102); Ultra-rare (popmax 0.0165%, mid).

How common is EAPP p.Pro173Leu (c.518C>T) in the general population?

EAPP p.Pro173Leu (c.518C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EAPP p.Pro173Leu (c.518C>T)?

AlphaMissense predicts ambiguous (score 0.4102) — an in-silico prediction, not a clinical call.

EAPP p.Pro173Leu

c.518C>T · VCV4662839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
AlphaMissense	0.4102	ambiguous
REVEL	0.332	indeterminate
SaProt	LLR -7.49	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.76 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000372% 6/1,612,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
South Asian	0.0033%	30,341
Admixed American	0.00167%	59,792
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: EAPP
Protein: p.Pro173Leu
Coding: c.518C>T
MANE Select: NM_018453
Type: single nucleotide variant
Location: chr14:34524760 (GRCh38)
Gene constraint: LOEUF 1.441 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.38

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

Similar variants

EAPP p.Arg239Gln Benign ★★ same type
EAPP p.Ala183Val Uncertain significance ★ ⚠ same type
EAPP p.Ala267Val Uncertain significance ★ ⚠ same type
EAPP p.Ala282Thr Uncertain significance ★ ⚠ same type
EAPP p.Ala95Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg156Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg229Ser Uncertain significance ★ ⚠ same type
EAPP p.Arg236Lys 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/eapp-p-pro173leu (accessed [today's date]).

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