Is AFP p.Val199Ala (c.596T>C) pathogenic?

AFP p.Val199Ala (c.596T>C) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0629); Very rare (popmax 0.00133%, afr).

How common is AFP p.Val199Ala (c.596T>C) in the general population?

AFP p.Val199Ala (c.596T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AFP p.Val199Ala (c.596T>C)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

AFP p.Val199Ala

c.596T>C · VCV4248705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -3.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -3.4
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	1.132	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 0.00133% African / African-American · 1/74,936 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,936
European (non-Finnish)	0.000254%	393,331

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.Val199Ala
Coding: c.596T>C
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73442409 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 199: a disulfide bond; the albumin 1 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-val199ala (accessed [today's date]).

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