Is MTAP p.Ala191Val (c.572C>T) pathogenic?

MTAP p.Ala191Val (c.572C>T) is classified Uncertain significance in MTAP (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-27). AlphaMissense: ambiguous (0.4133); Ultra-rare (popmax 0.0164%, mid); Associated with diaphyseal medullary stenosis-bone malignancy syndrome.

What condition is associated with MTAP p.Ala191Val (c.572C>T)?

MTAP p.Ala191Val (c.572C>T) is associated with diaphyseal medullary stenosis-bone malignancy syndrome (ClinVar).

How common is MTAP p.Ala191Val (c.572C>T) in the general population?

MTAP p.Ala191Val (c.572C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MTAP p.Ala191Val (c.572C>T)?

AlphaMissense predicts ambiguous (score 0.4133) — an in-silico prediction, not a clinical call.

MTAP p.Ala191Val

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.572C>T · rs200708704 · VCV638349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

diaphyseal medullary stenosis-bone malignancy syndrome

Computational evidence

Protein change
AlphaMissense	0.4133	ambiguous
REVEL	0.711	pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 59 kb · p 0.71 · regional, not allelic
Overall
CADD	26.2	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00874% 141/1,613,984 alleles · ultra-rare exomes 135/1,461,832 · genomes 6/152,152 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.01%	9,999
European (non-Finnish)	0.00949%	10,536
Finnishnot grpmax-eligible	0.00625%	16,008
East Asian	0.00445%	22,449
African / African-American	0.00401%	24,961
South Asian	0.0022%	45,543

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala191Val
Coding: c.572C>T
MANE Select: NM_002451
dbSNP: rs200708704
Type: single nucleotide variant
Location: chr9:21854752 (GRCh38)
Gene constraint: LOEUF 1.489 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 92.99 · 18 PDB

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-ala191val (accessed [today's date]).

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