Is MLIP p.Ser855Thr (c.2563T>A) pathogenic?

MLIP p.Ser855Thr (c.2563T>A) is classified Benign in MLIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-06). AlphaMissense: likely benign (0.0878); Common (popmax 94.5%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MLIP p.Ser855Thr (c.2563T>A)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

MLIP p.Ser855Thr

Q: How common is MLIP p.Ser855Thr (c.2563T>A) in the general population?

MLIP p.Ser855Thr (c.2563T>A) is common (popmax 94.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2563T>A · rs6934690 · VCV1249497

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 94.5%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 154 kb · p 0.0046 · regional, not allelic
Overall
CADD	18.98	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S320T vs ClinVar S855T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 94.5% European (non-Finnish) · 1,105,015/1,169,808 alleles

Filtering AF 94.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 94.3%

Overall 91.4% 1,463,637/1,601,458 alleles · common exomes 1,334,386/1,449,354 · genomes 129,251/152,104 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	94.9%	1
European (non-Finnish)grpmax	94.5%	1
Amishnot grpmax-eligible	93.8%	1
Remaining individualsnot grpmax-eligible	89.3%	1
South Asian	85%	1
Admixed American	84.1%	1
Ashkenazi Jewishnot grpmax-eligible	83.8%	1
Middle Eastern	80.4%	1
East Asian	78.2%	1
African / African-American	67.3%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MLIP
Protein: p.Ser855Thr
Coding: c.2563T>A
MANE Select: NM_001281747
dbSNP: rs6934690
Type: single nucleotide variant
Location: chr6:54189888 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 43.75

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

Similar variants

MLIP p.Asn14Tyr Uncertain significance ★★ same type
MLIP p.Thr581= Benign/Likely benign ★★ same type
MLIP c.2589+1G>A Likely pathogenic ★ same type
MLIP p.Arg844Ter Pathogenic ★ same type
MLIP p.Lys609Ter Pathogenic ★ same type
MLIP p.Ala764Pro Uncertain significance ★ same type
MLIP p.Ala941Asp Uncertain significance ★ ⚠ same type
MLIP p.Ala971Thr Uncertain significance ★ ⚠ same type

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/mlip-p-ser855thr (accessed [today's date]).

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