Is MTAP p.Val56Ile (c.166G>A) pathogenic?

MTAP p.Val56Ile (c.166G>A) is classified Benign in MTAP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-07-07). AlphaMissense: likely benign (0.1084); Common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with diaphyseal medullary stenosis-bone malignancy syndrome.

What condition is associated with MTAP p.Val56Ile (c.166G>A)?

MTAP p.Val56Ile (c.166G>A) is associated with diaphyseal medullary stenosis-bone malignancy syndrome (ClinVar).

What do computational predictors say about MTAP p.Val56Ile (c.166G>A)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

MTAP p.Val56Ile

Q: How common is MTAP p.Val56Ile (c.166G>A) in the general population?

MTAP p.Val56Ile (c.166G>A) is common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.166G>A · rs7023954 · VCV366238

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

diaphyseal medullary stenosis-bone malignancy syndrome

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -9.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 59 kb · p 0.71 · regional, not allelic
Overall
CADD	24.4	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 43.4% African / African-American · 32,359/74,632 alleles

Filtering AF 43% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.8%

Overall 40.7% 654,235/1,605,850 alleles · common exomes 591,018/1,453,922 · genomes 63,217/151,928 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.4%	2
Finnishnot grpmax-eligible	42.7%	2
Admixed American	42%	2
European (non-Finnish)	41.9%	2
East Asian	40.9%	2
Remaining individualsnot grpmax-eligible	39.4%	3
Ashkenazi Jewishnot grpmax-eligible	38.3%	3
Middle Eastern	28.3%	4
South Asian	23.5%	4
Amishnot grpmax-eligible	20.4%	5

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.Val56Ile
Coding: c.166G>A
MANE Select: NM_002451
dbSNP: rs7023954
Type: single nucleotide variant
Location: chr9:21816759 (GRCh38)
Gene constraint: LOEUF 1.489 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 92.99 · 18 PDB
Residue 56: a UniProt-annotated variant site (in); 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-val56ile (accessed [today's date]).

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