Is LAT p.Pro224Ser (c.670C>T) pathogenic?

LAT p.Pro224Ser (c.670C>T) is classified Uncertain significance in LAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.3949); Ultra-rare (popmax 0.0133%, amr).

How common is LAT p.Pro224Ser (c.670C>T) in the general population?

LAT p.Pro224Ser (c.670C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about LAT p.Pro224Ser (c.670C>T)?

AlphaMissense predicts ambiguous (score 0.3949) — an in-silico prediction, not a clinical call.

LAT p.Pro224Ser

c.670C>T · rs756999794 · VCV1420400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3949 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3949	ambiguous
REVEL	0.246	benign-leaning
SaProt	LLR -5.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,591 bp · p 0.0017 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P253S vs ClinVar P224S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,978 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00186% 30/1,613,626 alleles · ultra-rare exomes 27/1,461,532 · genomes 3/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
European (non-Finnish)	0.00186%	53,634

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: LAT
Protein: p.Pro224Ser
Coding: c.670C>T
MANE Select: NM_001014987
dbSNP: rs756999794
Type: single nucleotide variant
Location: chr16:28989980 (GRCh38)
Gene constraint: LOEUF 0.474 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 59.77
Residue 253 UniProt numbering: the 'disordered' region

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

Similar variants

LAT c.-41G>T Uncertain significance ★★ same type
LAT p.Ala183Val Uncertain significance ★★ ⚠ same type
LAT p.Arg53Gln Uncertain significance ★★ ⚠ same type
LAT p.Arg93Gln Uncertain significance ★★ ⚠ same type
LAT p.Arg93Trp Uncertain significance ★★ ⚠ same type
LAT p.Arg98Gln Uncertain significance ★★ ⚠ same type
LAT p.Arg98Trp Uncertain significance ★★ ⚠ same type
LAT p.Asp126Val 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/lat-p-pro224ser (accessed [today's date]).

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