Is AMH p.Leu339Pro (c.1016T>C) pathogenic?

AMH p.Leu339Pro (c.1016T>C) is classified Conflicting classifications of pathogenicity in AMH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-26). AlphaMissense: likely pathogenic (0.8603); Very rare (popmax 0.00512%, nfe); Associated with persistent Mullerian duct syndrome.

What condition is associated with AMH p.Leu339Pro (c.1016T>C)?

AMH p.Leu339Pro (c.1016T>C) is associated with persistent Mullerian duct syndrome, Cohen syndrome (ClinVar).

How common is AMH p.Leu339Pro (c.1016T>C) in the general population?

AMH p.Leu339Pro (c.1016T>C) is very rare (popmax 0.00512%, nfe) (gnomAD).

What do computational predictors say about AMH p.Leu339Pro (c.1016T>C)?

AlphaMissense predicts likely pathogenic (score 0.8603) — an in-silico prediction, not a clinical call.

AMH p.Leu339Pro

c.1016T>C · rs1012178126 · VCV1351018

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00512%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

persistent Mullerian duct syndrome

Computational evidence

Protein change
AlphaMissense	0.8603	likely pathogenic · top 9% in AMH
REVEL	0.675	pathogenic-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.92, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,621 bp · p 9.3e-15 · regional, not allelic
Overall
CADD	24.6	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 0.00512% European (non-Finnish) · 58/1,133,884 alleles

Filtering AF 0.00401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00367%

Overall 0.00419% 63/1,503,050 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00512%	19,550
Remaining individualsnot grpmax-eligible	0.00343%	29,153
East Asian	0.00271%	36,924
Admixed American	0.00209%	47,742
African / African-American	0.00145%	68,836

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: AMH
Protein: p.Leu339Pro
Coding: c.1016T>C
MANE Select: NM_000479
dbSNP: rs1012178126
Type: single nucleotide variant
Location: chr19:2251290 (GRCh38)
Gene constraint: LOEUF 1.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.40 · 3 PDB

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

Disease context

persistent Mullerian duct syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cohen syndrome

Similar variants

AMH p.Leu339fs Likely pathogenic ★ same residue
AMH p.Leu339= Likely benign ★ same residue
AMH p.Arg40Ter Pathogenic/Likely pathogenic ★★ same condition
AMH p.Gln217Ter Pathogenic/Likely pathogenic ★★ same condition
AMH p.Glu389Ter Pathogenic/Likely pathogenic ★★ same condition
AMH p.Gly101Arg Likely pathogenic ★★ same condition
AMH p.Pro151Ser Pathogenic ★★ ⚠ same condition
AMH p.Pro398Leu Uncertain significance ★★ ⚠ 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/amh-p-leu339pro (accessed [today's date]).

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