Is MTTP p.Ser305Leu (c.914C>T) pathogenic?

MTTP p.Ser305Leu (c.914C>T) is classified Likely benign in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0689); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with MTTP p.Ser305Leu (c.914C>T)?

MTTP p.Ser305Leu (c.914C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTTP p.Ser305Leu (c.914C>T) in the general population?

MTTP p.Ser305Leu (c.914C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about MTTP p.Ser305Leu (c.914C>T)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

MTTP p.Ser305Leu

c.914C>T · VCV3914511

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.071	GERP -3.2
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	7.588	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 0.00549% South Asian · 5/91,070 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000992% 16/1,613,682 alleles · very rare exomes 14/1,461,532 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,214
African / African-American	0.00534%	18,718
Admixed American	0.00167%	59,980
European (non-Finnish)	0.000509%	196,647

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: MTTP
Protein: p.Ser305Leu
Coding: c.914C>T
MANE Select: NM_001386140
Type: single nucleotide variant
Location: chr4:99597071 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.73 · 2 PDB
Residue 305: the vitellogenin domain; a turn

Full MTTP 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

MTTP p.Ser305= Conflicting classifications of pathogenicity ★ same residue
MTTP p.Ala144Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Ala339Val Uncertain significance ★★ ⚠ same condition
MTTP p.Ala464Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala493Ser Uncertain significance ★★ ⚠ same condition
MTTP p.Ala577Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala883Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Arg312Gly 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/mttp-p-ser305leu (accessed [today's date]).

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