Is METAP1 p.Pro210Ala (c.628C>G) pathogenic?

METAP1 p.Pro210Ala (c.628C>G) is classified Uncertain significance in METAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). AlphaMissense: likely benign (0.0756); Ultra-rare (popmax 0.0315%, eas).

How common is METAP1 p.Pro210Ala (c.628C>G) in the general population?

METAP1 p.Pro210Ala (c.628C>G) is ultra-rare (popmax 0.0315%, eas) (gnomAD).

What do computational predictors say about METAP1 p.Pro210Ala (c.628C>G)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

METAP1 p.Pro210Ala

c.628C>G · rs538234745 · VCV3125399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0315%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -10.30	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 66 kb · p 3.4e-05 · regional, not allelic
Overall
CADD	21.8	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 0.0315% East Asian · 14/44,484 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.000874% 14/1,602,538 alleles · ultra-rare exomes 9/1,450,306 · genomes 5/152,232 · joint denominator

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: METAP1
Protein: p.Pro210Ala
Coding: c.628C>G
MANE Select: NM_015143
dbSNP: rs538234745
Type: single nucleotide variant
Location: chr4:99043360 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 41 PDB

Full METAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP1A p.Arg2734Gln Uncertain significance ★★ same type
MAP1A p.Gly567Ala Uncertain significance ★★ ⚠ same type
MAP1A p.Gly482= Benign/Likely benign ★★ same type
MAP1A p.Leu1621Val Benign ★★ same type
MAP1A p.Ser1152= Likely benign ★★ same type
MAP1A p.Ser1311= Benign/Likely benign ★★ same type
MAP1A p.Ser1544= Benign ★★ same type
MAP1A p.Ser1858Cys 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/metap1-p-pro210ala (accessed [today's date]).

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