Is PSAT1 p.Pro126Ser (c.376C>T) pathogenic?

PSAT1 p.Pro126Ser (c.376C>T) is classified Uncertain significance in PSAT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-04-29). AlphaMissense: likely benign (0.1227); Very rare (popmax 0.00267%, afr); Associated with Neu-Laxova syndrome 2.

What condition is associated with PSAT1 p.Pro126Ser (c.376C>T)?

PSAT1 p.Pro126Ser (c.376C>T) is associated with Neu-Laxova syndrome 2 (ClinVar).

How common is PSAT1 p.Pro126Ser (c.376C>T) in the general population?

PSAT1 p.Pro126Ser (c.376C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PSAT1 p.Pro126Ser (c.376C>T)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

PSAT1 p.Pro126Ser

c.376C>T · rs1013336793 · VCV977034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Neu-Laxova syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.572	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.02 · regional, not allelic
Overall
CADD	20.6	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 0.00267% African / African-American · 2/74,850 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,612,490 alleles · very rare exomes 0/1,460,354 · genomes 3/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,425
Admixed American	0.00167%	59,996

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: PSAT1
Protein: p.Pro126Ser
Coding: c.376C>T
MANE Select: NM_058179
dbSNP: rs1013336793
Type: single nucleotide variant
Location: chr9:78304919 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 3 PDB
Residue 126: an α-helix

Full PSAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Neu-Laxova syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PSAT1 c.570+2T>C Likely pathogenic ★★ same condition
PSAT1 c.870-1G>T Pathogenic/Likely pathogenic ★★ same condition
PSAT1 p.Arg222Ter Pathogenic/Likely pathogenic ★★ same condition
PSAT1 p.Asp100Ala Pathogenic/Likely pathogenic ★★ same condition
PSAT1 p.Glu280Ter Pathogenic/Likely pathogenic ★★ same condition
PSAT1 p.Glu317Ter Pathogenic/Likely pathogenic ★★ same condition
PSAT1 p.Ala112Val Uncertain significance ★★ ⚠ same condition
PSAT1 p.Ala265Thr 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/psat1-p-pro126ser (accessed [today's date]).

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