Is CELSR1 p.Asp70His (c.208G>C) pathogenic?

CELSR1 p.Asp70His (c.208G>C) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1412); Ultra-rare (popmax 0.0241%, amr).

How common is CELSR1 p.Asp70His (c.208G>C) in the general population?

CELSR1 p.Asp70His (c.208G>C) is ultra-rare (popmax 0.0241%, amr) (gnomAD).

What do computational predictors say about CELSR1 p.Asp70His (c.208G>C)?

AlphaMissense predicts likely benign (score 0.1412) — an in-silico prediction, not a clinical call.

CELSR1 p.Asp70His

c.208G>C · VCV3490040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0241%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1412	likely benign
REVEL	0.026	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.1, phastCons 0.017
Regional constraint	o/e 1.06	unconstrained · MANE · 1,320 bp · p 0.15 · regional, not allelic
Overall
CADD	20.9	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 0.0241% Admixed American · 5/20,742 alleles

Filtering AF 0.00945% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00061% 7/1,147,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0241%	4,148
Remaining individualsnot grpmax-eligible	0.00257%	38,838
European (non-Finnish)	0.000107%	936,759

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: CELSR1
Protein: p.Asp70His
Coding: c.208G>C
MANE Select: NM_001378328
Type: single nucleotide variant
Location: chr22:46536963 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)

Full CELSR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR1 p.Ala2442Val Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala2955Thr Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala396Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala617Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1323Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1379His Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1720Trp 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/celsr1-p-asp70his (accessed [today's date]).

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