Is C8B p.Thr542Ile (c.1625C>T) pathogenic?

C8B p.Thr542Ile (c.1625C>T) is classified Likely benign in C8B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0589); Rare (popmax 0.953%, nfe).

How common is C8B p.Thr542Ile (c.1625C>T) in the general population?

C8B p.Thr542Ile (c.1625C>T) is rare (popmax 0.953%, nfe) (gnomAD).

What do computational predictors say about C8B p.Thr542Ile (c.1625C>T)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

C8B p.Thr542Ile

c.1625C>T · rs61737417 · VCV770848

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.953%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.6	GERP -0.35, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	5.88	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 0.953% European (non-Finnish) · 11,240/1,179,452 alleles

Filtering AF 0.938% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.932%

Overall 0.77% 12,420/1,613,466 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.64%	61
European (non-Finnish)grpmax	0.953%	105
Remaining individualsnot grpmax-eligible	0.714%	140
Admixed American	0.472%	212
Finnishnot grpmax-eligible	0.223%	448
South Asian	0.179%	559
African / African-American	0.139%	721
Middle Eastern	0.132%	756
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
East Asian	0.00223%	44,862

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr542Ile
Coding: c.1625C>T
MANE Select: NM_000066
dbSNP: rs61737417
Type: single nucleotide variant
Location: chr1:56929555 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 542: an α-helix; a disulfide bond; 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.Thr542= Likely benign ★ same residue
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

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-thr542ile (accessed [today's date]).

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