Is AFAP1L1 p.Val693Met (c.2077G>A) pathogenic?

AFAP1L1 p.Val693Met (c.2077G>A) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: ambiguous (0.3525); Very rare (popmax 0.00223%, eas).

How common is AFAP1L1 p.Val693Met (c.2077G>A) in the general population?

AFAP1L1 p.Val693Met (c.2077G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about AFAP1L1 p.Val693Met (c.2077G>A)?

AlphaMissense predicts ambiguous (score 0.3525) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Val693Met

c.2077G>A · rs1463628851 · VCV2480506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3525	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -8.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · regional, not allelic
Overall
CADD	29.2	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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,460,894 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	0.000339%	294,991

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.Val693Met
Coding: c.2077G>A
MANE Select: NM_152406
dbSNP: rs1463628851
Type: single nucleotide variant
Location: chr5:149332796 (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-val693met (accessed [today's date]).

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