Is CDH16 p.Phe77Leu (c.231C>G) pathogenic?

CDH16 p.Phe77Leu (c.231C>G) is classified Uncertain significance in CDH16 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.9098); Very rare (popmax 0.00267%, afr).

How common is CDH16 p.Phe77Leu (c.231C>G) in the general population?

CDH16 p.Phe77Leu (c.231C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CDH16 p.Phe77Leu (c.231C>G)?

AlphaMissense predicts likely pathogenic (score 0.9098) — an in-silico prediction, not a clinical call.

CDH16 p.Phe77Leu

c.231C>G · VCV4223711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9098	likely pathogenic · top 3% in CDH16
REVEL	0.312	indeterminate
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.32, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,670 bp · p 0.11 · regional, not allelic
Overall
CADD	23.2	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 0.00267% African / African-American · 2/74,958 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,268 alleles · very rare

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: CDH16
Protein: p.Phe77Leu
Coding: c.231C>G
MANE Select: NM_004062
Type: single nucleotide variant
Location: chr16:66916328 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.17
Residue 77: the cadherin 1 domain

Full CDH16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH16 p.Arg717His Benign ★★ same type
CDH16 p.Leu377= Benign ★★ same type
CDH16 p.Ala133Ser Uncertain significance ★ ⚠ same type
CDH16 p.Ala159Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala173Thr Uncertain significance ★ ⚠ same type
CDH16 p.Ala202Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala20Thr Uncertain significance ★ ⚠ same type
CDH16 p.Ala23Thr 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/cdh16-p-phe77leu (accessed [today's date]).

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