Is MFSD8 p.Arg5Pro (c.14G>C) pathogenic?

MFSD8 p.Arg5Pro (c.14G>C) is classified Uncertain significance in MFSD8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-20). AlphaMissense: likely benign (0.1127); Very rare (popmax 0.00534%, afr); Associated with neuronal ceroid lipofuscinosis 7.

What condition is associated with MFSD8 p.Arg5Pro (c.14G>C)?

MFSD8 p.Arg5Pro (c.14G>C) is associated with neuronal ceroid lipofuscinosis 7, late infantile neuronal ceroid lipofuscinosis (ClinVar).

How common is MFSD8 p.Arg5Pro (c.14G>C) in the general population?

MFSD8 p.Arg5Pro (c.14G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MFSD8 p.Arg5Pro (c.14G>C)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

MFSD8 p.Arg5Pro

c.14G>C · rs139409959 · VCV1192773

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 7

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -6.46	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 -0.37	GERP -3.2
Regional constraint	o/e 0.88	unconstrained · MANE · 44 kb · p 0.0019 · regional, not allelic
Overall
CADD	5.843	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 0.00534% African / African-American · 4/74,958 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,846 alleles · very rare exomes 1/1,461,588 · genomes 4/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,740
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: MFSD8
Protein: p.Arg5Pro
Coding: c.14G>C
MANE Select: NM_001371596
dbSNP: rs139409959
Type: single nucleotide variant
Location: chr4:127965120 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20
Residue 5: the 'disordered' region

Full MFSD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: late infantile neuronal ceroid lipofuscinosis

For CLN7 disease (Orphanet):

Onset: Infancy

Similar variants

MFSD8 p.Arg5= Conflicting classifications of pathogenicity ★ same residue
MFSD8 p.Arg5Gln Uncertain significance ★ ⚠ same residue
MFSD8 c.1102+1G>A Likely pathogenic ★★ same condition
MFSD8 c.1102+2T>C Pathogenic/Likely pathogenic ★★ same condition
MFSD8 c.1350+2T>C Pathogenic/Likely pathogenic ★★ same condition
MFSD8 c.154+1G>A Likely pathogenic ★★ same condition
MFSD8 c.198+2T>C Pathogenic/Likely pathogenic ★★ same condition
MFSD8 c.439+2T>A Likely pathogenic ★★ 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/mfsd8-p-arg5pro (accessed [today's date]).

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