Is F11 p.Pro66Ser (c.196C>T) pathogenic?

F11 p.Pro66Ser (c.196C>T) is classified Conflicting classifications of pathogenicity in F11 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-23). AlphaMissense: likely benign (0.0637); Ultra-rare (popmax 0.0825%, mid); Associated with Inborn genetic diseases.

What condition is associated with F11 p.Pro66Ser (c.196C>T)?

F11 p.Pro66Ser (c.196C>T) is associated with Inborn genetic diseases (ClinVar).

How common is F11 p.Pro66Ser (c.196C>T) in the general population?

F11 p.Pro66Ser (c.196C>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about F11 p.Pro66Ser (c.196C>T)?

AlphaMissense predicts likely benign (score 0.0637) — an in-silico prediction, not a clinical call.

F11 p.Pro66Ser

c.196C>T · rs144595035 · VCV3091389

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0637 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0637	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.04	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 -1	GERP -2.6
Overall
CADD	0.016	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 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00638% 103/1,614,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
Remaining individualsnot grpmax-eligible	0.0128%	7,814
European (non-Finnish)	0.00542%	18,438
Admixed American	0.00333%	30,009
African / African-American	0.00133%	75,050

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.Pro66Ser
Coding: c.196C>T
MANE Select: NM_000128
dbSNP: rs144595035
Type: single nucleotide variant
Location: chr4:186271749 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 117 PDB
Residue 66: the apple 1 domain; a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

F11 p.Asp69Gly Uncertain significance ★★ ⚠ same condition
F11 p.Ile537Leu Uncertain significance ★★ ⚠ same condition
F11 p.Thr407Ala Uncertain significance ★★ ⚠ same condition
F11 p.Val38Phe Uncertain significance ★★ ⚠ same condition
F11 p.Ala316Gly Uncertain significance ★ ⚠ same condition
F11 p.Ala337Thr Uncertain significance ★ ⚠ same condition
F11 p.Ala570Thr Uncertain significance ★ ⚠ same condition
F11 p.Arg154Met Uncertain significance ★ ⚠ same condition

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-pro66ser (accessed [today's date]).

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