Is METAP1 p.Ala355Val (c.1064C>T) pathogenic?

METAP1 p.Ala355Val (c.1064C>T) is classified Uncertain significance in METAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely pathogenic (0.969); Very rare (popmax 0.00364%, nfe).

How common is METAP1 p.Ala355Val (c.1064C>T) in the general population?

METAP1 p.Ala355Val (c.1064C>T) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about METAP1 p.Ala355Val (c.1064C>T)?

AlphaMissense predicts likely pathogenic (score 0.969) — an in-silico prediction, not a clinical call.

METAP1 p.Ala355Val

c.1064C>T · rs941318821 · VCV2611581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.969	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -12.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 66 kb · p 3.4e-05 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00364% European (non-Finnish) · 43/1,179,882 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00273% 44/1,613,852 alleles · very rare exomes 41/1,461,660 · genomes 3/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,439
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Ala355Val
Coding: c.1064C>T
MANE Select: NM_015143
dbSNP: rs941318821
Type: single nucleotide variant
Location: chr4:99061220 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 41 PDB
Residue 355: a β-strand

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-ala355val (accessed [today's date]).

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