Is AMH p.Thr99Ser (c.295A>T) pathogenic?

AMH p.Thr99Ser (c.295A>T) is classified Uncertain significance in AMH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1511); Ultra-rare (popmax 0.0477%, amr); Associated with persistent Mullerian duct syndrome.

What condition is associated with AMH p.Thr99Ser (c.295A>T)?

AMH p.Thr99Ser (c.295A>T) is associated with persistent Mullerian duct syndrome (ClinVar).

How common is AMH p.Thr99Ser (c.295A>T) in the general population?

AMH p.Thr99Ser (c.295A>T) is ultra-rare (popmax 0.0477%, amr) (gnomAD).

What do computational predictors say about AMH p.Thr99Ser (c.295A>T)?

AlphaMissense predicts likely benign (score 0.1511) — an in-silico prediction, not a clinical call.

AMH p.Thr99Ser

c.295A>T · rs200226465 · VCV1326605

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0477%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

persistent Mullerian duct syndrome

Computational evidence

Protein change
AlphaMissense	0.1511	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -6.04	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 2.5	GERP 1.2, phastCons 0.31
Regional constraint	o/e 1.27	unconstrained · MANE · 2,621 bp · p 9.3e-15 · regional, not allelic
Overall
CADD	15.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0477% Admixed American · 23/48,252 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0345%

Overall 0.0314% 481/1,529,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0477%	2,098
European (non-Finnish)	0.0387%	2,586
Remaining individualsnot grpmax-eligible	0.0272%	3,681
African / African-American	0.00138%	72,508

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.Thr99Ser
Coding: c.295A>T
MANE Select: NM_000479
dbSNP: rs200226465
Type: single nucleotide variant
Location: chr19:2249627 (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

Similar variants

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
AMH p.Thr268Ala Uncertain significance ★★ ⚠ same condition
AMH p.Ala86= Benign/Likely 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/amh-p-thr99ser (accessed [today's date]).

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