Is MEN1 p.Val185Ala (c.554T>C) pathogenic?

MEN1 p.Val185Ala (c.554T>C) is classified Conflicting classifications of pathogenicity in MEN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.497); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MEN1 p.Val185Ala (c.554T>C)?

MEN1 p.Val185Ala (c.554T>C) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 1 (ClinVar).

How common is MEN1 p.Val185Ala (c.554T>C) in the general population?

MEN1 p.Val185Ala (c.554T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MEN1 p.Val185Ala (c.554T>C)?

AlphaMissense predicts ambiguous (score 0.497) — an in-silico prediction, not a clinical call.

MEN1 p.Val185Ala

c.554T>C · rs764847812 · VCV457326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.497	ambiguous
REVEL	0.775	moderately pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,962 bp · p 4.4e-20 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V190A vs ClinVar V185A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,018 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,509
European (non-Finnish)	8.47e-05%	1,180,026

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: MEN1
Protein: p.Val185Ala
Coding: c.554T>C
MANE Select: NM_001370259
dbSNP: rs764847812
Type: single nucleotide variant
Location: chr11:64807991 (GRCh38)
Gene constraint: LOEUF 0.206 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.13 · 69 PDB
Residue 185: a β-strand

Full MEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 1

Similar variants

MEN1 p.Val185Leu Uncertain significance ★ ⚠ same residue
MEN1 p.Val185= Likely benign ★ same residue
MEN1 c.1049+1G>A Pathogenic ★★ same condition
MEN1 c.1049+1G>C Pathogenic ★★ same condition
MEN1 c.1049+2T>C Pathogenic/Likely pathogenic ★★ same condition
MEN1 c.1350+1G>A Pathogenic ★★ same condition
MEN1 c.1351-2A>C Pathogenic/Likely pathogenic ★★ same condition
MEN1 c.1351-2A>G Pathogenic ★★ 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/men1-p-val185ala (accessed [today's date]).

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