Is AMH p.Ser331Pro (c.991T>C) pathogenic?

AMH p.Ser331Pro (c.991T>C) is classified Conflicting classifications of pathogenicity in AMH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.6346); Rare (popmax 0.334%, afr).

How common is AMH p.Ser331Pro (c.991T>C) in the general population?

AMH p.Ser331Pro (c.991T>C) is rare (popmax 0.334%, afr) (gnomAD).

What do computational predictors say about AMH p.Ser331Pro (c.991T>C)?

AlphaMissense predicts likely pathogenic (score 0.6346) — an in-silico prediction, not a clinical call.

AMH p.Ser331Pro

c.991T>C · rs556078854 · VCV1337158

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6346 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.334%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6346	likely pathogenic
REVEL	0.73	pathogenic-leaning
SaProt	LLR -10.48	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 7.4	GERP 1, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,621 bp · p 9.3e-15 · regional, not allelic
Overall
CADD	24.8	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 0.334% African / African-American · 231/69,082 alleles

Filtering AF 0.299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.285%

Overall 0.0175% 264/1,505,426 alleles · rare exomes 125/1,353,418 · genomes 139/152,008 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.334%	299
Middle Eastern	0.0462%	2,166
Remaining individualsnot grpmax-eligible	0.0428%	2,338
Admixed American	0.00625%	15,994
South Asian	0.00124%	80,800
European (non-Finnish)	0.000176%	567,489

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.Ser331Pro
Coding: c.991T>C
MANE Select: NM_000479
dbSNP: rs556078854
Type: single nucleotide variant
Location: chr19:2251265 (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

Similar variants

AMH p.Ser331Leu Likely pathogenic ⚠ same residue
AMH p.Arg40Ter Pathogenic/Likely pathogenic ★★ same type
AMH p.Gln217Ter Pathogenic/Likely pathogenic ★★ same type
AMH p.Glu389Ter Pathogenic/Likely pathogenic ★★ same type
AMH p.Gly101Arg Likely pathogenic ★★ same type
AMH p.Pro151Ser Pathogenic ★★ ⚠ same type
AMH p.Trp371Ter Pathogenic ★★ same type
AMH p.Tyr167Cys Pathogenic ★★ ⚠ same type

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-ser331pro (accessed [today's date]).

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