Is AFAP1 p.Ile454Thr (c.1361T>C) pathogenic?

AFAP1 p.Ile454Thr (c.1361T>C) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4544); Very rare (popmax 0.00503%, amr).

How common is AFAP1 p.Ile454Thr (c.1361T>C) in the general population?

AFAP1 p.Ile454Thr (c.1361T>C) is very rare (popmax 0.00503%, amr) (gnomAD).

What do computational predictors say about AFAP1 p.Ile454Thr (c.1361T>C)?

AlphaMissense predicts ambiguous (score 0.4544) — an in-silico prediction, not a clinical call.

AFAP1 p.Ile454Thr

c.1361T>C · VCV4246795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4544 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Computational evidence

Protein change
AlphaMissense	0.4544	ambiguous
REVEL	0.421	indeterminate
SaProt	LLR -8.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 2.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	24.8	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 0.00503% Admixed American · 3/59,660 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000915%

Overall 0.000633% 10/1,579,604 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00503%	19,887
South Asian	0.00454%	22,008
African / African-American	0.00268%	37,338
Remaining individualsnot grpmax-eligible	0.00165%	60,668

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: AFAP1
Protein: p.Ile454Thr
Coding: c.1361T>C
MANE Select: NM_001134647
Type: single nucleotide variant
Location: chr4:7793732 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.09

Full AFAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1 p.Ile454Val Uncertain significance ★ ⚠ same residue
AFAP1 p.Val288Ala Uncertain significance ★★ ⚠ same type
AFAP1 p.Ala783= Likely benign ★★ same type
AFAP1 p.Asn686= Likely benign ★★ same type
AFAP1 p.Glu705= Benign ★★ same type
AFAP1 p.Ala438Ser Uncertain significance ★ ⚠ same type
AFAP1 p.Ala534Ser Uncertain significance ★ same type
AFAP1 p.Ala587Val 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/afap1-p-ile454thr (accessed [today's date]).

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