Is AFP p.Ile136Phe (c.406A>T) pathogenic?

AFP p.Ile136Phe (c.406A>T) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.086); Ultra-rare (popmax 0.0169%, nfe).

How common is AFP p.Ile136Phe (c.406A>T) in the general population?

AFP p.Ile136Phe (c.406A>T) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about AFP p.Ile136Phe (c.406A>T)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

AFP p.Ile136Phe

c.406A>T · rs544601167 · VCV2595416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.74	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 0.37	GERP -2.6
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	13.84	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 0.0169% European (non-Finnish) · 200/1,180,042 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0129% 209/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,900
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00534%	18,733

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.Ile136Phe
Coding: c.406A>T
MANE Select: NM_001134
dbSNP: rs544601167
Type: single nucleotide variant
Location: chr4:73440737 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 136: the albumin 1 domain

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-ile136phe (accessed [today's date]).

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