Is CD180 p.Leu76Phe (c.226C>T) pathogenic?

CD180 p.Leu76Phe (c.226C>T) is classified Uncertain significance in CD180 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2475); Very rare (popmax 0.00247%, nfe).

How common is CD180 p.Leu76Phe (c.226C>T) in the general population?

CD180 p.Leu76Phe (c.226C>T) is very rare (popmax 0.00247%, nfe) (gnomAD).

What do computational predictors say about CD180 p.Leu76Phe (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2475) — an in-silico prediction, not a clinical call.

CD180 p.Leu76Phe

c.226C>T · rs780734701 · VCV2508353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2475 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00247%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2475	likely benign
REVEL	0.657	pathogenic-leaning
SaProt	LLR -6.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 6.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 14 kb · p 0.097 · regional, not allelic
Overall
CADD	24.1	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 0.00247% European (non-Finnish) · 29/1,176,334 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.00193% 31/1,606,066 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00247%	40,563
African / African-American	0.00134%	74,636
South Asian	0.00112%	89,046

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: CD180
Protein: p.Leu76Phe
Coding: c.226C>T
MANE Select: NM_005582
dbSNP: rs780734701
Type: single nucleotide variant
Location: chr5:67185882 (GRCh38)
Gene constraint: LOEUF 1.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 1 PDB

Full CD180 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD180 p.Leu398= Benign ★★ same type
CD180 p.Ser584= Benign ★★ same type
CD180 p.Thr222= Benign ★★ same type
CD180 p.Thr430Ala Benign ★★ ⚠ same type
CD180 p.Ala415Ser Uncertain significance ★ ⚠ same type
CD180 p.Ala466Ser Uncertain significance ★ ⚠ same type
CD180 p.Ala649Thr Uncertain significance ★ ⚠ same type
CD180 p.Arg173Trp 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/cd180-p-leu76phe (accessed [today's date]).

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