Is EAPP p.Met73Thr (c.218T>C) pathogenic?

EAPP p.Met73Thr (c.218T>C) is classified Uncertain significance in EAPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.826); Ultra-rare (popmax 0.0331%, nfe).

How common is EAPP p.Met73Thr (c.218T>C) in the general population?

EAPP p.Met73Thr (c.218T>C) is ultra-rare (popmax 0.0331%, nfe) (gnomAD).

What do computational predictors say about EAPP p.Met73Thr (c.218T>C)?

AlphaMissense predicts likely pathogenic (score 0.826) — an in-silico prediction, not a clinical call.

EAPP p.Met73Thr

c.218T>C · rs200733425 · VCV2507581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.826 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.826	likely pathogenic
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	23.8	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 0.0331% European (non-Finnish) · 390/1,179,586 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0266% 429/1,612,202 alleles · ultra-rare exomes 402/1,460,092 · genomes 27/152,110 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0331%	3,025
Remaining individualsnot grpmax-eligible	0.0288%	3,469
Finnishnot grpmax-eligible	0.0203%	4,918
African / African-American	0.00802%	12,475
South Asian	0.00221%	45,193

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.Met73Thr
Coding: c.218T>C
MANE Select: NM_018453
dbSNP: rs200733425
Type: single nucleotide variant
Location: chr14:34536132 (GRCh38)
Gene constraint: LOEUF 1.441 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.38
Residue 73: the 'disordered' region

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-met73thr (accessed [today's date]).

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