Is AFP p.Val590Phe (c.1768G>T) pathogenic?

AFP p.Val590Phe (c.1768G>T) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely benign (0.0925); Very rare (popmax 0.00119%, nfe).

How common is AFP p.Val590Phe (c.1768G>T) in the general population?

AFP p.Val590Phe (c.1768G>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about AFP p.Val590Phe (c.1768G>T)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

AFP p.Val590Phe

c.1768G>T · VCV3504770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.83, phastCons 0.55
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00119% European (non-Finnish) · 14/1,179,708 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000868% 14/1,613,634 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: AFP
Protein: p.Val590Phe
Coding: c.1768G>T
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73453880 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 590: 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-val590phe (accessed [today's date]).

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