Is F11 p.Asp222Glu (c.666T>A) pathogenic?

F11 p.Asp222Glu (c.666T>A) is classified Uncertain significance in F11 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely pathogenic (0.6783); Ultra-rare (popmax 0.033%, mid).

How common is F11 p.Asp222Glu (c.666T>A) in the general population?

F11 p.Asp222Glu (c.666T>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about F11 p.Asp222Glu (c.666T>A)?

AlphaMissense predicts likely pathogenic (score 0.6783) — an in-silico prediction, not a clinical call.

F11 p.Asp222Glu

c.666T>A · rs1561483883 · VCV1704948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6783	likely pathogenic
REVEL	0.608	indeterminate
SaProt	LLR -9.62	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 -0.86	GERP -2.7, phastCons 0.001
Overall
CADD	14.51	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000205% 3/1,461,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
European (non-Finnish)	8.47e-05%	1,180,027

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: F11
Protein: p.Asp222Glu
Coding: c.666T>A
MANE Select: NM_000128
dbSNP: rs1561483883
Type: single nucleotide variant
Location: chr4:186276301 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 117 PDB
Residue 222: a disulfide bond; the apple 3 domain; a UniProt-annotated variant site (in fa11d)

Full F11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F11 p.Asp222Tyr Likely pathogenic ★★ same residue
F11 p.Asp222fs Likely pathogenic ★ same residue
F11 c.1136-1G>C Likely pathogenic ★★ same type
F11 c.1480+1G>T Likely pathogenic ★★ same type
F11 c.1481-1G>T Likely pathogenic ★★ same type
F11 c.1716+1G>A Pathogenic ★★ same type
F11 c.325+1G>A Pathogenic ★★ same type
F11 c.326-1G>A Pathogenic ★★ 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/f11-p-asp222glu (accessed [today's date]).

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