Is C8B p.Ser591Phe (c.1772C>T) pathogenic?

C8B p.Ser591Phe (c.1772C>T) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-26). AlphaMissense: likely benign (0.1666); Very rare (popmax 0.00167%, amr).

How common is C8B p.Ser591Phe (c.1772C>T) in the general population?

C8B p.Ser591Phe (c.1772C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C8B p.Ser591Phe (c.1772C>T)?

AlphaMissense predicts likely benign (score 0.1666) — an in-silico prediction, not a clinical call.

C8B p.Ser591Phe

c.1772C>T · rs1644662055 · VCV2079277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1666	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -4.45	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 -0.17	GERP -3.8
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	11.27	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,972 alleles

Overall 6.2e-05% 1/1,611,998 alleles · very rare exomes 0/1,459,806 · genomes 1/152,192 · joint denominator

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: C8B
Protein: p.Ser591Phe
Coding: c.1772C>T
MANE Select: NM_000066
dbSNP: rs1644662055
Type: single nucleotide variant
Location: chr1:56929408 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 591: the tsp type-1 2 domain; the 'disordered' region; a UniProt-annotated variant site (in c8d2)

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8B p.Arg284Ter Pathogenic ★★ same type
C8B p.Arg428Ter Pathogenic ★★ same type
C8B p.Cys508Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Trp9Ter Pathogenic ★★ same type
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same type
C8B p.Ala446Val Uncertain significance ★★ ⚠ same type
C8B p.Ala461Ser 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/c8b-p-ser591phe (accessed [today's date]).

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