Is MFSD8 p.Ile172Val (c.514A>G) pathogenic?

MFSD8 p.Ile172Val (c.514A>G) is classified Uncertain significance in MFSD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-15). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00266%, afr); Associated with neuronal ceroid lipofuscinosis 7.

What condition is associated with MFSD8 p.Ile172Val (c.514A>G)?

MFSD8 p.Ile172Val (c.514A>G) is associated with neuronal ceroid lipofuscinosis 7 (ClinVar).

How common is MFSD8 p.Ile172Val (c.514A>G) in the general population?

MFSD8 p.Ile172Val (c.514A>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about MFSD8 p.Ile172Val (c.514A>G)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

MFSD8 p.Ile172Val

c.514A>G · rs540305093 · VCV1428983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 7

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.57	donor gain · deltas
Pangolin	Δ0.39	gain · loss 0.22 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 44 kb · p 0.0019 · regional, not allelic
Overall
CADD	21.8	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 0.00266% African / African-American · 2/75,064 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,092 alleles · very rare exomes 3/1,461,744 · genomes 1/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,532
South Asian	0.0011%	91,090
European (non-Finnish)	8.47e-05%	1,179,970

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.Ile172Val
Coding: c.514A>G
MANE Select: NM_001371596
dbSNP: rs540305093
Type: single nucleotide variant
Location: chr4:127942084 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20

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

For CLN7 disease (Orphanet):

Onset: Infancy

Similar variants

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
MFSD8 c.440-2A>T Likely pathogenic ★★ same condition
MFSD8 c.553+1G>A Pathogenic/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-ile172val (accessed [today's date]).

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