Is AFAP1L1 p.Arg366Trp (c.1096C>T) pathogenic?

AFAP1L1 p.Arg366Trp (c.1096C>T) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely benign (0.1163); Very rare (popmax 0.00988%, sas).

How common is AFAP1L1 p.Arg366Trp (c.1096C>T) in the general population?

AFAP1L1 p.Arg366Trp (c.1096C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about AFAP1L1 p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Arg366Trp

c.1096C>T · rs374903729 · VCV3091769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP -2.1, phastCons 0.034
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · regional, not allelic
Overall
CADD	24.3	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 0.00988% South Asian · 9/91,072 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00167% 27/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,119
African / African-American	0.00801%	12,486
European (non-Finnish)	0.00102%	98,335

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: AFAP1L1
Protein: p.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_152406
dbSNP: rs374903729
Type: single nucleotide variant
Location: chr5:149315896 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.40

Full AFAP1L1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1L1 p.Ala110Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala130Gly Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala184Thr Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala582Thr Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala615Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala670Ser Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala674Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala721Thr 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/afap1l1-p-arg366trp (accessed [today's date]).

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