Is AFAP1L1 p.Pro123Arg (c.368C>G) pathogenic?

AFAP1L1 p.Pro123Arg (c.368C>G) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.3247); Ultra-rare (popmax 0.0316%, eas).

How common is AFAP1L1 p.Pro123Arg (c.368C>G) in the general population?

AFAP1L1 p.Pro123Arg (c.368C>G) is ultra-rare (popmax 0.0316%, eas) (gnomAD).

What do computational predictors say about AFAP1L1 p.Pro123Arg (c.368C>G)?

AlphaMissense predicts likely benign (score 0.3247) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Pro123Arg

c.368C>G · VCV3503429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0316%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3247	likely benign
REVEL	0.507	indeterminate
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · regional, not allelic
Overall
CADD	26.7	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 0.0316% East Asian · 14/44,314 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0153%

Overall 0.00138% 22/1,596,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0316%	3,165
Remaining individualsnot grpmax-eligible	0.00323%	30,952
European (non-Finnish)	0.000512%	195,308

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.Pro123Arg
Coding: c.368C>G
MANE Select: NM_152406
Type: single nucleotide variant
Location: chr5:149302458 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.40
Residue 123: the 'disordered' region

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

Similar variants

AFAP1L1 p.Pro123Ser Uncertain significance ★ ⚠ same residue
AFAP1L1 p.Pro123Thr 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

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-pro123arg (accessed [today's date]).

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