Is AFAP1L1 p.Arg591Cys (c.1771C>T) pathogenic?

AFAP1L1 p.Arg591Cys (c.1771C>T) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-29). AlphaMissense: likely benign (0.1068); Ultra-rare (popmax 0.0771%, nfe).

How common is AFAP1L1 p.Arg591Cys (c.1771C>T) in the general population?

AFAP1L1 p.Arg591Cys (c.1771C>T) is ultra-rare (popmax 0.0771%, nfe) (gnomAD).

What do computational predictors say about AFAP1L1 p.Arg591Cys (c.1771C>T)?

AlphaMissense predicts likely benign (score 0.1068) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Arg591Cys

c.1771C>T · rs114805975 · VCV2352563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0771%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1068	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · regional, not allelic
Overall
CADD	30.0	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 0.0771% European (non-Finnish) · 902/1,169,252 alleles

Filtering AF 0.0729% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0712%

Overall 0.0651% 1,037/1,593,742 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.177%	564
European (non-Finnish)grpmax	0.0771%	1,296
Remaining individualsnot grpmax-eligible	0.0227%	4,411
Admixed American	0.00867%	11,530
African / African-American	0.00401%	24,913
South Asian	0.00228%	43,794

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg591Cys
Coding: c.1771C>T
MANE Select: NM_152406
dbSNP: rs114805975
Type: single nucleotide variant
Location: chr5:149322678 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.40
Residue 591: the 'disordered' region

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-arg591cys (accessed [today's date]).

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