Is ACD p.Phe372Leu (c.1116C>G) pathogenic?

ACD p.Phe372Leu (c.1116C>G) is classified Uncertain significance in ACD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.6408); Very rare (popmax 8.65e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACD p.Phe372Leu (c.1116C>G)?

ACD p.Phe372Leu (c.1116C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACD p.Phe372Leu (c.1116C>G) in the general population?

ACD p.Phe372Leu (c.1116C>G) is very rare (popmax 8.65e-05%, nfe) (gnomAD).

What do computational predictors say about ACD p.Phe372Leu (c.1116C>G)?

AlphaMissense predicts likely pathogenic (score 0.6408) — an in-silico prediction, not a clinical call.

ACD p.Phe372Leu

c.1116C>G · rs1308443875 · VCV3232643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.65e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6408	likely pathogenic
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.64	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	3.748	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 8.65e-05% European (non-Finnish) · 1/1,156,722 alleles

Overall 0.000657% 1/152,184 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: ACD
Protein: p.Phe372Leu
Coding: c.1116C>G
MANE Select: NM_001082486
dbSNP: rs1308443875
Type: single nucleotide variant
Location: chr16:67658076 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB

Full ACD 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

ACD c.-20C>T Uncertain significance ★★ same condition
ACD c.-26T>G Uncertain significance ★★ same condition
ACD c.-29C>A Uncertain significance ★★ same condition
ACD c.-30C>T Uncertain significance ★★ same condition
ACD c.-35C>T Uncertain significance ★★ same condition
ACD c.-36C>G Uncertain significance ★★ same condition
ACD c.-9G>T Uncertain significance ★★ same condition
ACD p.Ala114Ser 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/acd-p-phe372leu (accessed [today's date]).

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