Is AFP p.Trp181Ter (c.543G>A) pathogenic?

AFP p.Trp181Ter (c.543G>A) is classified Pathogenic in AFP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-03-01). Ultra-rare (popmax 0.0133%, amr); Associated with Alpha-fetoprotein deficiency.

What condition is associated with AFP p.Trp181Ter (c.543G>A)?

AFP p.Trp181Ter (c.543G>A) is associated with Alpha-fetoprotein deficiency (ClinVar).

How common is AFP p.Trp181Ter (c.543G>A) in the general population?

AFP p.Trp181Ter (c.543G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

AFP p.Trp181Ter

c.543G>A · rs121912685 · VCV18170

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

Alpha-fetoprotein deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -3.7, phastCons 0.99
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,990 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00155% 25/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00127%	78,661

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.Trp181Ter
Coding: c.543G>A
MANE Select: NM_001134
dbSNP: rs121912685
Type: single nucleotide variant
Location: chr4:73442356 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 181: a disulfide bond; the albumin 1 domain; an α-helix

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

Disease context

Alpha-fetoprotein deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFP p.Thr547= Benign ★ same condition
AFP p.Leu295fs Pathogenic same condition
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

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-trp181ter (accessed [today's date]).

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