Is PHGDH p.Glu40Asp (c.120G>T) pathogenic?

PHGDH p.Glu40Asp (c.120G>T) is classified Uncertain significance in PHGDH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1477); Very rare (popmax 0.00769%, sas); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Glu40Asp (c.120G>T)?

PHGDH p.Glu40Asp (c.120G>T) is associated with PHGDH deficiency (ClinVar).

How common is PHGDH p.Glu40Asp (c.120G>T) in the general population?

PHGDH p.Glu40Asp (c.120G>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about PHGDH p.Glu40Asp (c.120G>T)?

AlphaMissense predicts likely benign (score 0.1477) — an in-silico prediction, not a clinical call.

PHGDH p.Glu40Asp

c.120G>T · rs745693493 · VCV1397494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PHGDH deficiency

Computational evidence

Protein change
AlphaMissense	0.1477	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	21.3	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 0.00769% South Asian · 7/91,086 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000479% 7/1,461,792 alleles · very rare

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: PHGDH
Protein: p.Glu40Asp
Coding: c.120G>T
MANE Select: NM_006623
dbSNP: rs745693493
Type: single nucleotide variant
Location: chr1:119712142 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB
Residue 40: an α-helix

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

Disease context

PHGDH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHGDH p.Glu40Gly Uncertain significance ★★ ⚠ same residue
PHGDH p.Glu40Ter Pathogenic ★ same residue
PHGDH p.Glu40Leu Uncertain significance ★ same residue
PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ 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/phgdh-p-glu40asp (accessed [today's date]).

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