Is NECTIN4 p.Pro104Arg (c.311C>G) pathogenic?

NECTIN4 p.Pro104Arg (c.311C>G) is classified Uncertain significance in NECTIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1057); Very rare (popmax 0.00446%, eas).

How common is NECTIN4 p.Pro104Arg (c.311C>G) in the general population?

NECTIN4 p.Pro104Arg (c.311C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about NECTIN4 p.Pro104Arg (c.311C>G)?

AlphaMissense predicts likely benign (score 0.1057) — an in-silico prediction, not a clinical call.

NECTIN4 p.Pro104Arg

c.311C>G · VCV4749277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1057	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -8.97	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 9,687 bp · p 0.02 · regional, not allelic
Overall
CADD	23.6	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000373% 6/1,609,028 alleles · very rare exomes 4/1,456,772 · genomes 2/152,256 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
Admixed American	0.00167%	59,980
South Asian	0.0011%	91,068
European (non-Finnish)	0.00017%	589,890

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: NECTIN4
Protein: p.Pro104Arg
Coding: c.311C>G
MANE Select: NM_030916
Type: single nucleotide variant
Location: chr1:161079718 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 79.79 · 5 PDB
Residue 104: the ig-like v-type domain

Full NECTIN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NECTIN4 p.Pro104Thr Benign ★★ ⚠ same residue
NECTIN4 p.Asn489Asp Uncertain significance ★★ ⚠ same type
NECTIN4 p.Glu8Lys Uncertain significance ★★ ⚠ same type
NECTIN4 p.Met436Val Uncertain significance ★★ ⚠ same type
NECTIN4 p.Pro463Ala Uncertain significance ★★ ⚠ same type
NECTIN4 p.Thr497Met Uncertain significance ★★ ⚠ same type
NECTIN4 c.1000+18A>G Benign ★★ same type
NECTIN4 p.Arg284= 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/nectin4-p-pro104arg (accessed [today's date]).

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