Is EXOC7 p.Ser556Phe (c.1667C>T) pathogenic?

EXOC7 p.Ser556Phe (c.1667C>T) is classified Uncertain significance in EXOC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: ambiguous (0.3411); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXOC7 p.Ser556Phe (c.1667C>T)?

EXOC7 p.Ser556Phe (c.1667C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOC7 p.Ser556Phe (c.1667C>T) in the general population?

EXOC7 p.Ser556Phe (c.1667C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about EXOC7 p.Ser556Phe (c.1667C>T)?

AlphaMissense predicts ambiguous (score 0.3411) — an in-silico prediction, not a clinical call.

EXOC7 p.Ser556Phe

c.1667C>T · VCV3510974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3411	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -8.18	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 4,423 bp · p 4.4e-05 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S607F vs ClinVar S556F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,178,938 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,457,858 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: EXOC7
Protein: p.Ser556Phe
Coding: c.1667C>T
MANE Select: NM_001013839
Type: single nucleotide variant
Location: chr17:76085359 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.41

Full EXOC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOC7 p.Ser556Tyr Uncertain significance ★ same residue
EXOC7 p.Ser556Pro Uncertain significance ★ ⚠ same residue
EXOC7 p.Gln390Leu Uncertain significance ★★ ⚠ same condition
EXOC7 p.Val218Ile Uncertain significance ★★ ⚠ same condition
EXOC7 c.901+656A>G Likely benign ★★ same condition
EXOC7 p.Gln349Ter Pathogenic ★ same condition
EXOC7 c.127-5C>T Uncertain significance ★ same condition
EXOC7 c.417+2T>G Uncertain significance ★ same condition

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/exoc7-p-ser556phe (accessed [today's date]).

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