Is AMH p.Cys488Arg (c.1462T>C) pathogenic?

AMH p.Cys488Arg (c.1462T>C) is classified Uncertain significance in AMH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-06). AlphaMissense: likely pathogenic (0.9935); Very rare (popmax 8.48e-05%, nfe).

How common is AMH p.Cys488Arg (c.1462T>C) in the general population?

AMH p.Cys488Arg (c.1462T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about AMH p.Cys488Arg (c.1462T>C)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

AMH p.Cys488Arg

c.1462T>C · VCV3655795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic · top 1% in AMH
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -15.78	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 7.6	GERP 1, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,621 bp · p 9.3e-15 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,524 alleles

Overall 6.85e-05% 1/1,459,554 alleles · very rare

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.Cys488Arg
Coding: c.1462T>C
MANE Select: NM_000479
Type: single nucleotide variant
Location: chr19:2251736 (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 488: a disulfide bond; a β-strand

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

Similar variants

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
AMH p.Ala78Thr 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-cys488arg (accessed [today's date]).

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