Is EXOC4 p.Pro751Ser (c.2251C>T) pathogenic?

EXOC4 p.Pro751Ser (c.2251C>T) is classified Uncertain significance in EXOC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0934); Very rare (popmax 0.00653%, nfe).

How common is EXOC4 p.Pro751Ser (c.2251C>T) in the general population?

EXOC4 p.Pro751Ser (c.2251C>T) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about EXOC4 p.Pro751Ser (c.2251C>T)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

EXOC4 p.Pro751Ser

c.2251C>T · VCV4251905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.55	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 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 811 kb · p 0.018 · regional, not allelic
Overall
CADD	20.2	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 0.00653% European (non-Finnish) · 77/1,179,810 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00502% 81/1,613,646 alleles · very rare exomes 73/1,461,480 · genomes 8/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,322
Admixed American	0.00334%	29,967
Remaining individualsnot grpmax-eligible	0.0016%	62,452
South Asian	0.0011%	91,074

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: EXOC4
Protein: p.Pro751Ser
Coding: c.2251C>T
MANE Select: NM_021807
Type: single nucleotide variant
Location: chr7:133997536 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.22 · 1 PDB

Full EXOC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOC4 p.Pro751Thr Uncertain significance ★ ⚠ same residue
EXOC4 p.Gly550Arg Benign ★★ ⚠ same type
EXOC4 p.Ile926= Benign ★★ same type
EXOC4 p.Leu749= Benign ★★ same type
EXOC4 p.Pro20= Benign ★★ same type
EXOC4 c.1417+54940G>A Uncertain significance ★ same type
EXOC4 p.Ala153Val Uncertain significance ★ ⚠ same type
EXOC4 p.Ala225Asp 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/exoc4-p-pro751ser (accessed [today's date]).

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