Is AFP p.Leu334Ser (c.1001T>C) pathogenic?

AFP p.Leu334Ser (c.1001T>C) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely benign (0.1911); Ultra-rare (popmax 0.0387%, afr).

How common is AFP p.Leu334Ser (c.1001T>C) in the general population?

AFP p.Leu334Ser (c.1001T>C) is ultra-rare (popmax 0.0387%, afr) (gnomAD).

What do computational predictors say about AFP p.Leu334Ser (c.1001T>C)?

AlphaMissense predicts likely benign (score 0.1911) — an in-silico prediction, not a clinical call.

AFP p.Leu334Ser

c.1001T>C · VCV3274878

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1911	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.23	donor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	25.7	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 0.0387% African / African-American · 29/74,962 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00223% 36/1,611,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,585
Middle Eastern	0.0214%	4,672
Remaining individualsnot grpmax-eligible	0.00642%	15,578
South Asian	0.0011%	90,960
European (non-Finnish)	8.48e-05%	1,179,654

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.Leu334Ser
Coding: c.1001T>C
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73447619 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 334: the albumin 2 domain; a β-strand

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-leu334ser (accessed [today's date]).

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