Is AFP p.Leu553Pro (c.1658T>C) pathogenic?

AFP p.Leu553Pro (c.1658T>C) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.935); Absent from gnomAD v4.1.

How common is AFP p.Leu553Pro (c.1658T>C) in the general population?

AFP p.Leu553Pro (c.1658T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFP p.Leu553Pro (c.1658T>C)?

AlphaMissense predicts likely pathogenic (score 0.935) — an in-silico prediction, not a clinical call.

AFP p.Leu553Pro

c.1658T>C · VCV4638777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.935	likely pathogenic · top 1% in AFP
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -13.75	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFP
Protein: p.Leu553Pro
Coding: c.1658T>C
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73453770 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 553: a disulfide bond; the albumin 3 domain; an α-helix

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

Similar variants

AFP c.714-5C>T Likely benign ★★ same type
AFP p.Ser286= Benign ★★ same type
AFP p.Ser445= Benign ★★ same type
AFP p.Gly608Arg Likely pathogenic ★ ⚠ same type
AFP p.Ala134Val Uncertain significance ★ ⚠ same type
AFP p.Ala471Val Uncertain significance ★ ⚠ same type
AFP p.Ala476Thr Uncertain significance ★ ⚠ same type
AFP p.Ala476Val 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/afp-p-leu553pro (accessed [today's date]).

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