Is C8B p.Phe125Leu (c.375T>G) pathogenic?

C8B p.Phe125Leu (c.375T>G) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-03). AlphaMissense: likely pathogenic (0.9802); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C8B p.Phe125Leu (c.375T>G)?

C8B p.Phe125Leu (c.375T>G) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Phe125Leu (c.375T>G) in the general population?

C8B p.Phe125Leu (c.375T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C8B p.Phe125Leu (c.375T>G)?

AlphaMissense predicts likely pathogenic (score 0.9802) — an in-silico prediction, not a clinical call.

C8B p.Phe125Leu

c.375T>G · rs2522781743 · VCV1955420

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9802 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9802	likely pathogenic · top 1% in C8B
REVEL	0.695	pathogenic-leaning
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.33	GERP -4.6
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	20.9	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

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: C8B
Protein: p.Phe125Leu
Coding: c.375T>G
MANE Select: NM_000066
dbSNP: rs2522781743
Type: single nucleotide variant
Location: chr1:56956785 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 125: a disulfide bond; a UniProt-annotated variant site (in c8d2); a β-strand; the ldl-receptor class a domain

Full C8B 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

C8B p.Ala21Thr Uncertain significance ★★ ⚠ same condition
C8B p.Ala446Val Uncertain significance ★★ ⚠ same condition
C8B p.Arg136Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His Uncertain significance ★★ ⚠ same condition
C8B p.Arg156Gly Uncertain significance ★★ ⚠ same condition
C8B p.Arg296Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg296His Uncertain significance ★★ ⚠ same condition
C8B p.Arg428Gln 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/c8b-p-phe125leu (accessed [today's date]).

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