Is F8 p.Pro170Ser (c.508C>T) pathogenic?

F8 p.Pro170Ser (c.508C>T) is classified Conflicting classifications of pathogenicity in F8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-30). AlphaMissense: likely benign (0.1801); Very rare (popmax 0.00179%, nfe).

How common is F8 p.Pro170Ser (c.508C>T) in the general population?

F8 p.Pro170Ser (c.508C>T) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about F8 p.Pro170Ser (c.508C>T)?

AlphaMissense predicts likely benign (score 0.1801) — an in-silico prediction, not a clinical call.

F8 p.Pro170Ser

c.508C>T · rs782458440 · VCV2920835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1801	likely benign
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -10.04	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	22.4	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 0.00179% European (non-Finnish) · 16/895,232 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000856%

Overall 0.00146% 16/1,097,927 alleles · very rare

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: F8
Protein: p.Pro170Ser
Coding: c.508C>T
MANE Select: NM_000132
dbSNP: rs782458440
Type: single nucleotide variant
Location: chrX:154993029 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 170: the f5/8 type a 1 domain; the plastocyanin-like 1 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F8 p.Pro170Leu Uncertain significance ★ ⚠ same residue
F8 p.Pro170His Uncertain significance ★ same residue
F8 c.6429+2T>A Pathogenic ★★★ same type
F8 p.Ala111Thr Likely pathogenic ★★★ same type
F8 p.Ala2220Pro Pathogenic ★★★ same type
F8 p.Ala415Asp Likely pathogenic ★★★ same type
F8 p.Ala415Val Pathogenic ★★★ ⚠ same type
F8 p.Arg1768His 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/f8-p-pro170ser (accessed [today's date]).

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