Is AFAP1 p.Arg676Ser (c.2028A>C) pathogenic?

AFAP1 p.Arg676Ser (c.2028A>C) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9485); Absent from gnomAD v4.1.

How common is AFAP1 p.Arg676Ser (c.2028A>C) in the general population?

AFAP1 p.Arg676Ser (c.2028A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFAP1 p.Arg676Ser (c.2028A>C)?

AlphaMissense predicts likely pathogenic (score 0.9485) — an in-silico prediction, not a clinical call.

AFAP1 p.Arg676Ser

c.2028A>C · VCV4246984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9485 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9485	likely pathogenic · top 7% in AFAP1
REVEL	0.3	indeterminate
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP -3.9
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	10.42	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R592S vs ClinVar R676S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFAP1
Protein: p.Arg676Ser
Coding: c.2028A>C
MANE Select: NM_001134647
Type: single nucleotide variant
Location: chr4:7774773 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.09

Full AFAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1 p.Val288Ala Uncertain significance ★★ ⚠ same type
AFAP1 p.Ala783= Likely benign ★★ same type
AFAP1 p.Asn686= Likely benign ★★ same type
AFAP1 p.Glu705= Benign ★★ same type
AFAP1 p.Ala438Ser Uncertain significance ★ ⚠ same type
AFAP1 p.Ala534Ser Uncertain significance ★ same type
AFAP1 p.Ala587Val Uncertain significance ★ same type
AFAP1 p.Ala624Val 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/afap1-p-arg676ser (accessed [today's date]).

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