Is CEP43 p.Phe89Leu (c.267T>G) pathogenic?

CEP43 p.Phe89Leu (c.267T>G) is classified Uncertain significance in CEP43 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: likely pathogenic (0.9909); Ultra-rare (popmax 0.0218%, nfe).

How common is CEP43 p.Phe89Leu (c.267T>G) in the general population?

CEP43 p.Phe89Leu (c.267T>G) is ultra-rare (popmax 0.0218%, nfe) (gnomAD).

What do computational predictors say about CEP43 p.Phe89Leu (c.267T>G)?

AlphaMissense predicts likely pathogenic (score 0.9909) — an in-silico prediction, not a clinical call.

CEP43 p.Phe89Leu

c.267T>G · rs140062109 · VCV3142932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9909	likely pathogenic · top 2% in CEP43
REVEL	0.396	indeterminate
SaProt	LLR -12.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	phastCons 0.009
Regional constraint	o/e 1.07	unconstrained · MANE · 41 kb · p 0.13 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0218% European (non-Finnish) · 257/1,178,430 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0246% 396/1,611,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.24%	416
Remaining individualsnot grpmax-eligible	0.0433%	2,310
Finnishnot grpmax-eligible	0.0361%	2,773
European (non-Finnish)grpmax	0.0218%	4,585
Middle Eastern	0.0165%	6,048
South Asian	0.011%	9,098
Admixed American	0.00833%	12,002
African / African-American	0.00267%	37,504

Ashkenazi Jewish 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: CEP43
Protein: p.Phe89Leu
Coding: c.267T>G
MANE Select: NM_007045
dbSNP: rs140062109
Type: single nucleotide variant
Location: chr6:167003778 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.69 · 1 PDB
Residue 89: the lish domain; an α-helix

Full CEP43 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP43 p.Ala148Val Uncertain significance ★ ⚠ same type
CEP43 p.Ala39Gly Uncertain significance ★ ⚠ same type
CEP43 p.Ala6Val Uncertain significance ★ ⚠ same type
CEP43 p.Ala79Glu Uncertain significance ★ ⚠ same type
CEP43 p.Arg112Gln Uncertain significance ★ ⚠ same type
CEP43 p.Arg134Cys Uncertain significance ★ ⚠ same type
CEP43 p.Arg134Gly Uncertain significance ★ ⚠ same type
CEP43 p.Arg17Trp 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/cep43-p-phe89leu (accessed [today's date]).

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