Is AMH p.Pro158fs (c.472_485del) pathogenic?

AMH p.Pro158fs (c.472485del) is classified Pathogenic in AMH (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-27). Very rare (popmax 0.00205%, nfe).

How common is AMH p.Pro158fs (c.472_485del) in the general population?

AMH p.Pro158fs (c.472_485del) is very rare (popmax 0.00205%, nfe) (gnomAD).

AMH p.Pro158fs

c.472_485del · rs774592796 · VCV8623

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00205%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.3	GERP 0.79, phastCons 1
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00205% European (non-Finnish) · 24/1,169,634 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00164% 26/1,589,214 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00325%	30,765
European (non-Finnish)grpmax	0.00205%	48,735

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: AMH
Protein: p.Pro158fs
Coding: c.472_485del
MANE Select: NM_000479
dbSNP: rs774592796
Type: Deletion
Location: chr19:2250388 (GRCh38)
Gene constraint: LOEUF 1.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.40 · 3 PDB
Residue 158: a disulfide bond

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

Similar variants

AMH p.Pro158Ser Uncertain significance ★ ⚠ same residue
AMH p.Leu70fs Pathogenic ★★ same type
AMH p.Gln51fs Pathogenic ★ same type
AMH p.Leu112fs Likely pathogenic ★ same type
AMH p.Leu9fs Pathogenic ★ same type
AMH p.Arg560fs Uncertain significance ★ 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-pro158fs (accessed [today's date]).

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