Is AMZ2 p.Ser55Phe (c.164C>T) pathogenic?

AMZ2 p.Ser55Phe (c.164C>T) is classified Uncertain significance in AMZ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.4327); Very rare (popmax 0.00446%, eas).

How common is AMZ2 p.Ser55Phe (c.164C>T) in the general population?

AMZ2 p.Ser55Phe (c.164C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about AMZ2 p.Ser55Phe (c.164C>T)?

AlphaMissense predicts ambiguous (score 0.4327) — an in-silico prediction, not a clinical call.

AMZ2 p.Ser55Phe

c.164C>T · VCV4093974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4327	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -9.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 6,778 bp · p 0.078 · regional, not allelic
Overall
CADD	26.8	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,894 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: AMZ2
Protein: p.Ser55Phe
Coding: c.164C>T
MANE Select: NM_016627
Type: single nucleotide variant
Location: chr17:68250351 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.55

Full AMZ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMZ2 p.Ser55Pro Uncertain significance ★ ⚠ same residue
AMZ2 p.Ala117Thr Uncertain significance ★ ⚠ same type
AMZ2 p.Ala269Val Uncertain significance ★ ⚠ same type
AMZ2 p.Arg101Lys Uncertain significance ★ ⚠ same type
AMZ2 p.Arg247Gln Uncertain significance ★ ⚠ same type
AMZ2 p.Arg263Gln Uncertain significance ★ ⚠ same type
AMZ2 p.Arg283Trp Uncertain significance ★ ⚠ same type
AMZ2 p.Arg284Pro 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/amz2-p-ser55phe (accessed [today's date]).

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