Is MFSD8 p.Pro412Ser (c.1234C>T) pathogenic?

MFSD8 p.Pro412Ser (c.1234C>T) is classified Uncertain significance in MFSD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-18). AlphaMissense: likely benign (0.3248); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with MFSD8 p.Pro412Ser (c.1234C>T)?

MFSD8 p.Pro412Ser (c.1234C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MFSD8 p.Pro412Ser (c.1234C>T) in the general population?

MFSD8 p.Pro412Ser (c.1234C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MFSD8 p.Pro412Ser (c.1234C>T)?

AlphaMissense predicts likely benign (score 0.3248) — an in-silico prediction, not a clinical call.

MFSD8 p.Pro412Ser

c.1234C>T · rs2546046689 · VCV1756403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3248	likely benign
REVEL	0.689	pathogenic-leaning
SaProt	LLR -10.20	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 44 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.6	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 0.0011% South Asian · 1/91,086 alleles

Overall 6.2e-05% 1/1,614,164 alleles · very rare exomes 1/1,461,872 · genomes 0/152,292 · joint denominator

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.Pro412Ser
Coding: c.1234C>T
MANE Select: NM_001371596
dbSNP: rs2546046689
Type: single nucleotide variant
Location: chr4:127921640 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20
Residue 412: a UniProt-annotated variant site (in cln7)

Full MFSD8 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

MFSD8 p.Pro412Leu Pathogenic/Likely pathogenic ★★ same residue
MFSD8 p.Pro412= Uncertain significance ★ same residue
MFSD8 p.Pro412Ala Uncertain significance ⚠ same residue
MFSD8 c.863+1G>A Pathogenic ★★ same condition
MFSD8 p.Ala146Thr Uncertain significance ★★ ⚠ same condition
MFSD8 p.Ala257Thr Uncertain significance ★★ ⚠ same condition
MFSD8 p.Ala406Gly Uncertain significance ★★ ⚠ same condition
MFSD8 p.Arg21Ser 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/mfsd8-p-pro412ser (accessed [today's date]).

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