Is AFAP1L1 p.Arg683Trp (c.2047C>T) pathogenic?

AFAP1L1 p.Arg683Trp (c.2047C>T) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: ambiguous (0.4851); Ultra-rare (popmax 0.0524%, mid).

How common is AFAP1L1 p.Arg683Trp (c.2047C>T) in the general population?

AFAP1L1 p.Arg683Trp (c.2047C>T) is ultra-rare (popmax 0.0524%, mid) (gnomAD).

What do computational predictors say about AFAP1L1 p.Arg683Trp (c.2047C>T)?

AlphaMissense predicts ambiguous (score 0.4851) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Arg683Trp

c.2047C>T · VCV4247114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0524%, mid)

Computational evidence

Protein change
AlphaMissense	0.4851	ambiguous
REVEL	0.296	indeterminate
SaProt	LLR -9.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -1.4, phastCons 0.93
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · 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 0.0524% Middle Eastern · 3/5,724 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0076%

Overall 0.00167% 27/1,613,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0524%	1,908
East Asian	0.00445%	22,447
African / African-American	0.00267%	37,463
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,444
European (non-Finnish)	0.00153%	65,557

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.Arg683Trp
Coding: c.2047C>T
MANE Select: NM_152406
Type: single nucleotide variant
Location: chr5:149332766 (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.Arg683Gln Uncertain significance ★ ⚠ same residue
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

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-arg683trp (accessed [today's date]).

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