Is AFP p.Thr294Ile (c.881C>T) pathogenic?

AFP p.Thr294Ile (c.881C>T) is classified Likely benign in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0669); Ultra-rare (popmax 0.0869%, afr).

How common is AFP p.Thr294Ile (c.881C>T) in the general population?

AFP p.Thr294Ile (c.881C>T) is ultra-rare (popmax 0.0869%, afr) (gnomAD).

What do computational predictors say about AFP p.Thr294Ile (c.881C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

AFP p.Thr294Ile

c.881C>T · rs144523159 · VCV2319744

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -4.58	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 -6.3	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	0.002	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 0.0869% African / African-American · 65/74,790 alleles

Filtering AF 0.0699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0638%

Overall 0.00447% 72/1,611,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0869%	1,151
Middle Eastern	0.0179%	5,592
Remaining individualsnot grpmax-eligible	0.00481%	20,791
Admixed American	0.00167%	59,780
European (non-Finnish)	0.00017%	589,577

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.Thr294Ile
Coding: c.881C>T
MANE Select: NM_001134
dbSNP: rs144523159
Type: single nucleotide variant
Location: chr4:73447499 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 294: a disulfide bond; the albumin 2 domain; a turn

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-thr294ile (accessed [today's date]).

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