Is AFAP1L2 p.Arg648His (c.1943G>A) pathogenic?

AFAP1L2 p.Arg648His (c.1943G>A) is classified Uncertain significance in AFAP1L2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1221); Very rare (popmax 0.00466%, nfe).

How common is AFAP1L2 p.Arg648His (c.1943G>A) in the general population?

AFAP1L2 p.Arg648His (c.1943G>A) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about AFAP1L2 p.Arg648His (c.1943G>A)?

AlphaMissense predicts likely benign (score 0.1221) — an in-silico prediction, not a clinical call.

AFAP1L2 p.Arg648His

c.1943G>A · rs200106844 · VCV2369236

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1221	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.93	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 2.1	GERP -2.2, phastCons 0.065
Regional constraint	o/e 1.02	unconstrained · MANE · 8,830 bp · p 0.56 · regional, not allelic
Overall
CADD	13.69	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 0.00466% European (non-Finnish) · 55/1,180,048 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.016% 258/1,614,090 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.605%	165
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)grpmax	0.00466%	21,455
African / African-American	0.004%	24,978

Ashkenazi Jewish 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: AFAP1L2
Protein: p.Arg648His
Coding: c.1943G>A
MANE Select: NM_001001936
dbSNP: rs200106844
Type: single nucleotide variant
Location: chr10:114300208 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.56 · 1 PDB

Full AFAP1L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1L2 p.Arg730= Benign/Likely benign ★★ same type
VWA2 p.Arg682Trp Benign ★★ ⚠ same type
VWA2 p.Asn331= Benign ★★ same type
VWA2 p.Gly641= Likely benign ★★ same type
VWA2 p.His496Tyr Benign ★★ same type
VWA2 p.Phe365= Benign ★★ same type
VWA2 p.Pro544= Benign ★★ same type
VWA2 p.Val366Met Benign ★★ ⚠ 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/afap1l2-p-arg648his (accessed [today's date]).

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