Is MTAP p.Ala218Val (c.653C>T) pathogenic?

MTAP p.Ala218Val (c.653C>T) is classified Benign in MTAP (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1585); Ultra-rare (popmax 0.0866%, afr); Associated with diaphyseal medullary stenosis-bone malignancy syndrome.

What condition is associated with MTAP p.Ala218Val (c.653C>T)?

MTAP p.Ala218Val (c.653C>T) is associated with diaphyseal medullary stenosis-bone malignancy syndrome (ClinVar).

How common is MTAP p.Ala218Val (c.653C>T) in the general population?

MTAP p.Ala218Val (c.653C>T) is ultra-rare (popmax 0.0866%, afr) (gnomAD).

What do computational predictors say about MTAP p.Ala218Val (c.653C>T)?

AlphaMissense predicts likely benign (score 0.1585) — an in-silico prediction, not a clinical call.

MTAP p.Ala218Val

Q: How is Diaphyseal medullary stenosis-bone malignancy syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.653C>T · rs143080527 · VCV366247

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diaphyseal medullary stenosis-bone malignancy syndrome

Computational evidence

Protein change
AlphaMissense	0.1585	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -9.86	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 59 kb · p 0.71 · regional, not allelic
Overall
CADD	24.2	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 0.0866% African / African-American · 65/75,022 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00799% 129/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0866%	1,154
Admixed American	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0144%	6,945
European (non-Finnish)	0.00339%	29,499
South Asian	0.0022%	45,538
Finnishnot grpmax-eligible	0.00156%	64,010

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: MTAP
Protein: p.Ala218Val
Coding: c.653C>T
MANE Select: NM_002451
dbSNP: rs143080527
Type: single nucleotide variant
Location: chr9:21854833 (GRCh38)
Gene constraint: LOEUF 1.489 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 92.99 · 18 PDB
Residue 218: a β-strand

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

Disease context

diaphyseal medullary stenosis-bone malignancy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Diaphyseal medullary stenosis-bone malignancy syndrome (Orphanet):

Inheritance: Autosomal dominant

Similar variants

MTAP c.*1453C>T Uncertain significance ★★ same condition
MTAP p.Gln75Arg Uncertain significance ★★ ⚠ same condition
MTAP c.121-10T>C Benign ★★ same condition
MTAP c.179+12T>A Benign/Likely benign ★★ same condition
MTAP c.*2085G>A Benign ★★ same condition
MTAP c.*2365C>T Benign ★★ same condition
MTAP c.*2522A>G Benign ★★ same condition
MTAP c.*258A>C Benign ★★ same condition

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/mtap-p-ala218val (accessed [today's date]).

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