Is CDH4 p.Val116Met (c.346G>A) pathogenic?

CDH4 p.Val116Met (c.346G>A) is classified Likely benign in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.0165%, mid).

How common is CDH4 p.Val116Met (c.346G>A) in the general population?

CDH4 p.Val116Met (c.346G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CDH4 p.Val116Met (c.346G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

CDH4 p.Val116Met

c.346G>A · rs760527005 · VCV2515209

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.97	GERP -3.1
Regional constraint	o/e 1.05	unconstrained · MANE · 521 kb · p 0.43 · regional, not allelic
Overall
CADD	1.346	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.0041% 66/1,610,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	0.00484%	20,681
Remaining individualsnot grpmax-eligible	0.00481%	20,781
African / African-American	0.00267%	37,520
South Asian	0.00222%	45,094
Admixed American	0.00168%	59,682

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: CDH4
Protein: p.Val116Met
Coding: c.346G>A
MANE Select: NM_001794
dbSNP: rs760527005
Type: single nucleotide variant
Location: chr20:61743739 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02

Full CDH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same type
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same type
CDH4 c.1629-8C>T Benign ★★ same type
CDH4 c.2240-4A>G Benign ★★ same type
CDH4 p.Ala33Thr Benign ★★ same type
CDH4 p.Ala344= Benign/Likely benign ★★ same type
CDH4 p.Asn283= Benign/Likely benign ★★ same type
CDH4 p.Asn450= Benign/Likely benign ★★ 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/cdh4-p-val116met (accessed [today's date]).

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